ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review)
In 2025, seven fluorine-containing anticancer agents received approval from the US Food and Drug Administration, underscoring the continued and growing impact of strategic fluorination in modern oncology drug design. These newly authorized therapies represent a diverse portfolio spanning a broad spe...
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| Дата: | 2026 |
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| Формат: | Стаття |
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V.I.Vernadsky Institute of General and Inorganic Chemistry
2026
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Ukrainian Chemistry Journal| _version_ | 1871466228939227136 |
|---|---|
| author | Wzorek, Alicja Ono, Taizo Klika, Karel Lyutenko , Natalia Soloshonok, Vadim |
| author_facet | Wzorek, Alicja Ono, Taizo Klika, Karel Lyutenko , Natalia Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Karel Klika",
"institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany"
},
{
"author": "Natalia Lyutenko ",
"institution": "V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, The National Academy of Sciences of Ukraine, Acad. Kukharya Street, 02094 Kyiv, Ukraine"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Wzorek, Alicja |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:57Z |
| description | In 2025, seven fluorine-containing anticancer agents received approval from the US Food and Drug Administration, underscoring the continued and growing impact of strategic fluorination in modern oncology drug design. These newly authorized therapies represent a diverse portfolio spanning a broad spectrum of malignancies, molecular targets, and innovative mechanisms of action, further validating fluorine’s unique ability to enhance drug performance. Sunvozertinib (Zegfrovy®) was approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring specific EGFR mutations. The combination of defactinib and avutometinib (Avmapki®) provides a much-needed targeted option for patients with KRAS-mutated recurrent low-grade serous ovarian cancer, addressing a historically challenging disease setting. Imlunestrant (Inluriyo®) offers a next-generation selective estrogen receptor degrader (SERD) as an effective endocrine therapy for estrogen receptor-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Ziftomenib (Komzifti®) enables precision therapy for adults with relapsed or refractory (AML) carrying susceptible NPM1 mutations, representing a significant advancement in targeted hematologic oncology.Datopotamab deruxtecan (Datroway®), a novel TROP2-directed antibody–drug conjugate (ADC) with a topoisomerase I inhibitor payload, expands treatment options for previously treated hormone receptor-positive, HER2-negative metastatic breast cancer and for certain TKI-experienced NSCLC populations. Taletrectinib (Ibtrozi®), a potent next-generation ROS1 tyrosine kinase inhibitor, received approval for ROS1-positive NSCLC in both TKI-naïve and TKI-experienced patients, offering improved central nervous system penetration and activity against resistant mutations.Collectively, these seven agents vividly illustrate the remarkable versatility of fluorine incorporation in enhancing molecular potency, metabolic stability, binding selectivity, and overall pharmacokinetic performance across vastly different therapeutic modalities — from small-molecule kinase inhibitors and degraders to complex antibody–drug conjugates. The strategic placement of fluorine atoms or fluorinated groups in these molecules often leads to improved lipophilicity, stronger target engagement, reduced clearance, and better safety profiles.For each compound, we provide a comprehensive integrated discussion covering its discovery history, detailed biological mechanism of action, primary therapeutic applications, recommended clinical administration and dosing regimens, the specific role of fluorination in optimizing its pharmacological and physicochemical properties, as well as the detailed chemical synthesis routes employed in its industrial-scale production. |
| doi_str_mv | 10.33609/2708-129X.92.4.2026.52-78 |
| first_indexed | 2026-06-04T01:00:20Z |
| format | Article |
| fulltext |
52 ISSN 2708-129X. Укр. хім. журн., 2025
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.92.4.2026.52-78
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY:
A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS
IN 2025 (review).
Alicja Wzorek1 https://orcid.org/0000-0001-9041-7034
Taizo Ono2 https://orcid.org/0009-0002-3268-2344
Karel D. Klika3 https://orcid.org/0000-0001-7009-1487
Nataliya V. Lyutenko4 https://orcid.org/0000-0003-3538-2814
Vadim A. Soloshonok5* https://orcid.org/0000-0003-0681-4526
1 Institute of Chemistry, Jan Kochanowski University in Kielce,
Uniwersytecka 7, 25-406 Kielce, Poland;
2 National Institute of Advanced Industrial Science and Technology (AIST),
2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan;
3 Hamburg Advanced Research Center for Bioorganic Chemistry (HARBOR), Universität Hamburg,
Luruper Chaussee 149, 22761 Hamburg, Germany;
4 Department of Fine Organic Synthesis, V.P. Kukhar Institute of Bioorganic Chemistry
and Petrochemistry, The National Academy of Sciences of Ukraine,
1 Murmanska str., Kyiv 02094, Ukraine;
5 IKERBASQUE, Basque Foundation for Science,
María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain
e-mail: vadimsoloshonok@gmail.com
In 2025, seven fluorine-containing anticancer agents received approval from the US Food and
Drug Administration, underscoring the continued and growing impact of strategic fluorination
in modern oncology drug design. These newly authorized therapies represent a diverse portfolio
spanning a broad spectrum of malignancies, molecular targets, and innovative mechanisms of
action, further validating fluorine’s unique ability to enhance drug performance. Sunvozertinib
(Zegfrovy®) was approved for the treatment of locally advanced or metastatic non-small cell lung
cancer (NSCLC) harboring specific EGFR mutations. The combination of defactinib and avu-
tometinib (Avmapki®) provides a much-needed targeted option for patients with KRAS-mutated
recurrent low-grade serous ovarian cancer, addressing a historically challenging disease setting.
Imlunestrant (Inluriyo®) offers a next-generation selective estrogen receptor degrader (SERD)
as an effective endocrine therapy for estrogen receptor-positive, HER2-negative, ESR1-mutated
advanced or metastatic breast cancer. Ziftomenib (Komzifti®) enables precision therapy for adults
with relapsed or refractory (AML) carrying susceptible NPM1 mutations, representing a signi
ficant advancement in targeted hematologic oncology.Datopotamab deruxtecan (Datroway®), a
novel TROP2-directed antibody–drug conjugate (ADC) with a topoisomerase I inhibitor pay-
load, expands treatment options for previously treated hormone receptor-positive, HER2-nega-
tive metastatic breast cancer and for certain TKI-experienced NSCLC populations. Taletrectinib
53https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Karel D. Klika, Nataliya V. Lyutenko, Vadim A. Soloshonok UCJ № 4/ Vol. 92
(Ibtrozi®), a potent next-generation ROS1 tyrosine kinase inhibitor, received approval for ROS1-
positive NSCLC in both TKI-naïve and TKI-experienced patients, offering improved central ner
vous system penetration and activity against resistant mutations.Collectively, these seven agents
vividly illustrate the remarkable versatility of fluorine incorporation in enhancing molecular po-
tency, metabolic stability, binding selectivity, and overall pharmacokinetic performance across
vastly different therapeutic modalities — from small-molecule kinase inhibitors and degraders
to complex antibody–drug conjugates. The strategic placement of fluorine atoms or fluorinated
groups in these molecules often leads to improved lipophilicity, stronger target engagement, re-
duced clearance, and better safety profiles.For each compound, we provide a comprehensive inte-
grated discussion covering its discovery history, detailed biological mechanism of action, primary
therapeutic applications, recommended clinical administration and dosing regimens, the specific
role of fluorination in optimizing its pharmacological and physicochemical properties, as well as
the detailed chemical synthesis routes employed in its industrial-scale production.
Key words: Fluorine; Drug Design; Oncology; Synthesis; Chirality; Pharmacology; Therapeutics.
Dedication: Dedicated to the memory of Professor
Volodymyr Brovarets whose rare combination of
intellect, kindness, and curiosity enriched every-
one around him. Your legacy remains alive in our
hearts and in the science you loved.
INTRODUCTION. Pharmaceutical drugs
are essential to modern civilization, profoundly
shaping public health and quality of life. They
treat and manage a wide range of acute and
chronic diseases, from bacterial infections–
transformed by antibiotics in the modern
era–to long-term conditions such as diabetes,
hypertension, and cardiovascular disorders.
Advances in oncology, including chemothe
rapy and targeted therapies, have markedly im-
proved survival rates while vaccines have near
eradicated or greatly reduced the incidence of
a number of once devastating infectious di
seases [1–3].
Beyond disease control, pharmaceuticals
enhance daily functioning by relieving pain,
managing symptoms, and supporting mental
health, enabling individuals with depression,
anxiety, or chronic pain to participate fully
in society. They are indispensable to modern
medical practice—surgery, transplantation,
and intensive care all rely on anesthesia, im-
munosuppressants, and other critical drugs.
Pharmaceuticals also underpin public health
initiatives, including vaccination and disease-
control programs. Continuous research and
development within the pharmaceutical in-
dustry drives the discovery of new therapies
ensuring progress against emerging health
challenges [4–6].
Fluorine is a key element in modern drug
design owing to properties that significant-
ly enhance therapeutic performance [7–10].
By blocking metabolic oxidation sites, fluorine
slows drug degradation, extending half-life,
and sustaining efficacy. Its strong electronega-
tivity fine tunes molecular electronics, impro
ving interactions with biological targets and
54 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
increasing potency and selectivity. Fluorine in-
corporation can also enhance solubility, mem-
brane permeability, and overall bioavailability,
helping drugs reach their intended sites more
effectively while reducing off-target effects
[11–15].
Comprehensive surveys over the past
25 years [7, 16–22] indicate that more than
450 fluorine-containing pharmaceuticals have
been approved by the US Food and Drug Ad-
ministration (FDA). Structurally, heterocyclic
scaffolds dominate modern drug design, ap-
pearing in over 85% of approved agents due to
their broad biological activities and exception-
al versatility as molecular backbones [23–31].
Amino acid-derived motifs are similarly in-
fluential: over 30% of small-molecule drugs
incorporate amino acid residues or related de-
rivatives such as amino alcohols and diamines.
These fragments expand structural diversity
and, by introducing defined stereochemistry,
enable three-dimensional architectures that
optimize target engagement [32–41]. Chirality
is also very much a central principle of drug
design with more than 70% of marketed phar-
maceuticals chiral [42–46].
From a therapeutic perspective, fluorinated
drugs span nearly all major disease areas. The
most frequent activities include anticancer,
anti-infective, antiviral, anti-inflammatory,
cardiovascular, metabolic, and central nervous
system (CNS) indications [7, 14, 16]. Among
these, anticancer agents represent one of the
most prominent and rapidly expanding cate
gories. Fluorination is especially valuable in
oncology because it enhances metabolic sta-
bility, improves target selectivity, and enables
the fine tuning of physicochemical properties
required for potent inhibition of oncogenic
pathways. Many landmark cancer therapeu-
tics—including fluoropyrimidines, kinase in-
hibitors, and modern targeted agents—rely
on strategic fluorine incorporation to achieve
clinical efficacy [7, 14, 16].
In this review, we profile seven recently ap-
proved fluorine-containing, anti-cancer drugs
approved by the US FDA in the year 2025.
These include sunvozertinib (Zegfrovy®) 1
(Fig. 1), approved for treatment in adults with
locally advanced or metastatic non-small cell
lung cancer (NSCLC). Defactinib 2 and avu-
tometinib (Avmapki®) 3, a co-approved oral
combination regimen, are indicated for adults
with KRAS-mutated recurrent low-grade se-
rous ovarian cancer (LGSOC) after prior sys-
temic therapy. Imlunestrant (Inluriyo®) 4 is
indicated for adults with estrogen receptor
(ER)-positive, HER2-negative, ESR1-mutated
advanced or metastatic breast cancer that has
progressed after at least one line of endocrine
therapy. Ziftomenib (Komzifti®) 5 is approved
for adults with relapsed or refractory acute
myeloid leukemia (AML) harboring suscep-
tible NPM1 mutations. Datopotamab derux-
tecan (Datroway®) 6 is a TROP2-directed an-
tibody–drug conjugate (ADC) approved for
adults with unresectable or metastatic hor-
mone receptor-positive, HER2-negative breast
cancer after prior endocrine therapy and
chemotherapy, and for certain adults with pre-
viously treated advanced NSCLC. Taletrecti
nib (Ibtrozi®) 7 is indicated for adults with
locally advanced or metastatic ROS1-positive
NSCLC, including both TKI-naïve and
TKI-experienced patients. For each drug, we
outline its discovery, mechanism of biological
activity, and detailed synthetic route. We also
assess, when possible, how fluorination influ-
ences the drug’s biological profile.
55https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Karel D. Klika, Nataliya V. Lyutenko, Vadim A. Soloshonok UCJ № 4/ Vol. 92
Fig. 1. Fluorine-containing oncologics that have been introduced
into the pharmaceutical market in 2025.
EXPERIMENT AND DISCUSSION OF
THE RESULTS. Sunvozertinib (Zegfrovy©,
DZD9008) 1 is an oral, irreversible, pyrimi-
dine-based epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitor (TKI) deve
loped by Dizal (Jiangsu) Pharmaceutical Co.,
Ltd. It represents the first approved targeted
oral therapy specifically designed to address
the therapeutic challenges posed by EGFR
exon 20 insertion mutations (exon20ins) in
NSCLC [47].
Sunvozertinib 1 was discovered through
rational, structure-guided medicinal chemis-
try optimization starting from the osimerti-
nib 8 (Fig. 2) scaffold. The design focused on
overcoming the unique steric hindrance and
conformational constraints introduced by
exon20ins in the EGFR kinase domain while
preserving high potency against a wide spect
rum of EGFR exon20ins variants and mini
mizing off-target activity against wild-type
EGFR. Preclinical evaluation demonstrated
56 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
potent enzymatic and cellular inhibition of di-
verse EGFR exon20ins (as well as classical sen-
sitizing mutations and T790M) coupled with
robust antitumor efficacy in patient-derived
xenograft models and favorable pharmacoki-
netic properties [48, 49].
Fig. 2. Structure of osimertinib 8.
Following promising preclinical data, sun-
vozertinib 1 entered clinical development with
a phase 1 dose-escalation and expansion study
that established initial safety, pharmacokinetics,
and preliminary antitumor activity in heavily
pre-treated EGFR exon20ins NSCLC patients,
including those with prior monoclonal anti-
body amivantamab exposure or baseline brain
metastases. Pivotal efficacy was subsequently
demonstrated in two key phase 2 trials: the sin-
gle-arm WU-KONG6 study conducted in Chi-
na and the multinational, open-label, dose-ran-
domized WU-KONG1B global study. These re-
sults supported regulatory milestones, including
Breakthrough Therapy Designation by both the
US FDA and China’s National Medical Products
Administration (NMPA). Sunvozertinib 1 re-
ceived accelerated approval in China in August
2023 (the first oral agent targeted for this indica-
tion worldwide) and accelerated approval by the
US FDA in July 2025 [47].
Sunvozertinib 1 is indicated for the treat-
ment of adult patients with locally advanced or
metastatic NSCLC harboring EGFR exon20ins
(as detected by a US FDA-approved test) whose
disease has progressed during or after plati-
num-based chemotherapy. It fills a longstand-
ing unmet need in this molecularly defined sub-
group (approximately 1–4% of NSCLC) which
has historically exhibited intrinsic resistance
to earlier-generation EGFR TKIs and limited
post-platinum options [48, 49].
The recommended dose is 200 mg orally
administered once daily, taken with food and
swallowed whole, until disease progression or
unacceptable toxicity results. Dose reductions
to 150 mg are recommended for selected grade
≥ 3 adverse reactions (e.g., severe gastrointes-
tinal or dermatologic toxicities) with perma-
nent discontinuation indicated for interstitial
lung disease/pneumonitis or intolerance to the
reduced dose. Administration with food was
found to improve tolerability and exposure
consistency [50, 51].
In the primary efficacy population of the
pivotal WU-KONG1B trial (n = 85 patients
treated with the approved 200 mg dose), sun-
vozertinib 1 achieved a confirmed objective
response rate (ORR) of 46% (95% CI: 35–57%;
6% complete response, 40% partial response)
by blinded, independent central review per
RECIST v1.1 with a median duration of response
(DOR) of 11.1 months (95% CI: 8.2–not estima-
ble); 72% of responses lasted ≥ 6 months. Effi-
cacy was consistent across subgroups, includ-
ing patients with baseline brain metastases and
prior amivantamab treatment. Supporting data
from the Chinese WU-KONG6 trial (300 mg
cohort, n = 97) showed a higher ORR of 61%
(95% CI: 50–71%) with responses observed ir-
respective of exon20ins variant subtype, prior
lines of therapy, or immunotherapy exposure.
These outcomes establish sunvozertinib 1 as a
clinically meaningful advance for a previously
difficult-to-treat population [50, 51].
57https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Karel D. Klika, Nataliya V. Lyutenko, Vadim A. Soloshonok UCJ № 4/ Vol. 92
Fluorine and chlorine atoms were intro-
duced to address oxidative metabolic liability
identified on the unsubstituted phenyl ring of
earlier leads. Thus, dual 4-fluoro- and 5-chloro
substitution reduced human hepatocyte clear-
ance from 34 to 7.1 μL/min per 10⁶ cells—a >
4-fold improvement–while preserving EGFR
mutant activity [48]. The fluorine atom plays
a particularly critical role in metabolic stabi
lity. By blocking para-hydroxylation (a major
CYP-mediated oxidative pathway on the ani-
line ring), the 4-fluoro substituent markedly
improves systemic exposure and oral bioavai
lability without compromising target engage-
ment. In co-crystal modeling (PDB 4LRM
overlay), the fluorine atom projects toward
the solvent-accessible region and does not
form direct polar interactions with the protein;
its primary contribution is pharmacokinetic
rather than direct binding affinity. The paired
5-chloro substitution further augments steric
and electronic modulation, collectively ena-
bling the low clearance required for once-daily
oral dosing at the approved 200 mg level. These
halogens also subtly tune electron density on
the aniline NH group, supporting optimal
hinge and back-pocket interactions, but the
dominant bioactivity benefit documented in
the discovery SAR is the dramatic reduction in
metabolic turnover [48, 49].
The synthesis of sunvozertinib 1 from
the commercially available and inexpensive
starting materials 2-(2-amino-4-chloro-5-
fluorophenyl)propan-2-ol (9) and 2,4-dichlo-
ropyrimidine (10) is outlined in Scheme 1
[52,53]. Nucleophilic aromatic substitution
between 9 and 10, conducted in isopropanol at
90 °C for 27 h in the presence of the non-nu-
cleophilic base N,N-diisopropylethylamine
(DIPEA) [54] afforded intermediate 11 in
50% yield. A second SNAr reaction of 11 with
4-fluoro-2-methoxy-5-nitrobenzenamine (12)
was performed under acidic conditions (tri-
fluoroacetic acid, TFA) in n-butanol at 50 °C
for 26 h, delivering the core aromatic scaffold
13 in 86% yield. Functional elaboration of in-
termediate 13 was achieved in three final steps.
First, reaction with (R)-N,N-dimethylpyrro-
lidin-3-amine (14) under basic conditions
in DMSO at temperatures up to 50 °C for 5 h
furnished intermediate 15 in 87% yield. Subse-
quent reduction of the nitro group in 15 using
Zn/NH4Cl in methanol–H2O at 90 °C for 2 h
provided aniline derivative 16 in 63% yield.
The synthesis concluded with acylation of the
amine in 16 using acryloyl chloride 17 in the
presence of DIPEA in dimethyl formamide
(DMF) at 5–10 °C for 30 min affording sun-
vozertinib 1 in high yield. Overall, this route
features operationally simple transformations,
mild and easily controlled reaction conditions,
and is readily scalable for the preparation of
sunvozertinib 1 in process-relevant quantities.
Defactinib 2 (VS-6063) is a selective inhibi
tor of focal adhesion kinase (FAK), a non-re-
ceptor tyrosine kinase involved in cell adhe-
sion, migration, survival, and cancer stem
cell maintenance. It was discovered and deve
loped by Verastem Oncology, with additional
clinical research support from the National
Cancer Institute and several academic cancer
centers. Over the past decade, defactinib 2 has
advanced through numerous clinical studies,
including more than thirty trials evaluating its
activity across a range of solid tumors [55].
The therapeutic rationale for defactinib 2
centers on the role of FAK signaling in tumor
progression, metastasis, and the survival of
cancer stem cell populations. Its principal areas
of clinical investigation include low-grade
58 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
serous ovarian cancer, pancreatic cancer, and
endometrial cancer, often in combination with
avutometinib 3, a RAF/MEK inhibitor. The
combination of defactinib 2 and avutometinib
3 has received US FDA Orphan Drug Designa-
tion for metastatic pancreatic cancer, reflecting
its potential in RAS/MAPK-driven malignan-
cies. Additional exploratory studies have exa
mined its activity in glioblastoma, mesothelio-
ma, and breast cancer [56].
Scheme 1. Synthesis of sunvozertinib 1.
Defactinib 2 is administered orally. In its
most clinically advanced regimen, it is given
at a dose of 200 mg twice daily on days 1–21
of a 28-day cycle in combination with avutom-
etinib 3. In early glioblastoma studies, single
preoperative doses of 200–400 mg were used
to assess tumor penetration and pharmacody-
namic effects.
Preclinical studies demonstrate potent inhi-
bition of FAK and Pyk2, suppression of cancer
stem cell populations, and significant tumor
growth inhibition in xenograft models. Clini-
cal data further support its activity. In RAMP
205, a pancreatic cancer study, the combination
of defactinib 2, avutometinib 3, and standard
chemotherapy produced partial responses in
most evaluable patients with substantial re-
ductions in target lesion size and a managea-
ble safety profile. In glioblastoma, defactinib 2
was detectable in tumor tissue within hours of
administration and produced a marked reduc-
tion in Pyk2 phosphorylation confirming tar-
get engagement [57].
In defactinib 2, the CF3 group on the pyri
midine ring plays an important role in po-
tency, stability, and overall pharmacological
59https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Karel D. Klika, Nataliya V. Lyutenko, Vadim A. Soloshonok UCJ № 4/ Vol. 92
behavior. The CF3 substituent is a very strong
electron-withdrawing group, and on a hetero
aromatic core it modulates the electronics of
the hinge-binding region in a way that im-
proves hydrogen-bond geometry, π-stacking,
and polarization of nearby heteroatoms. These
effects typically strengthen kinase binding,
which is consistent with the behavior of fluo
rinated pyridines and pyrimidines in medicinal
chemistry. The CF3 group also increases meta-
bolic stability. Because it strongly resists oxida-
tive metabolism, it blocks common metabolic
soft spots such as aromatic hydroxylation and
N-oxidation. This generally leads to improved
half-life and better systemic exposure, which
is desirable for an orally administered kinase
inhibitor [58,59].
Overall, these findings position defactinib
2 as a promising component of combination
regimens targeting tumors driven by aberrant
FAK and RAS/MAPK signaling, with ongoing
development focused on ovarian and panc
reatic cancers [55–60].
The synthetic route to defactinib 2 relies on the
convergent assembly of two key intermediates,
21 and 24, as outlined in Scheme 2 [61]. The se-
quence begins with nucleophilic aromatic sub-
stitution between 3-chloropyrazine-2-carboni-
trile (18) and N-methyl methanesulfonamide
(19) under basic conditions in acetonitrile to
afford adduct 20. Subsequent catalytic hydro
genation of the nitrile group in 20 over Pd/C
in the presence of ammonia furnishes cleanly
the corresponding primary amine 21. In a pa
rallel branch, 2,4-dichloro-5-(trifluoromethyl)
pyrimidine (22) undergoes selective displace-
ment of the chlorine located on C-4 by the
amino group of 4-amino-N-methylbenzamide
(23) to generate intermediate 24. The final step
involves coupling amine 21 with pyrimidine 24
Scheme 2. Synthesis of defactinib 2.
60 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
via another nucleophilic aromatic substitution
in 1,2-dichloroethane (DCE)–t-BuOH using
DIPEA as a non-nucleophilic base to provide
defactinib 2. Overall, this synthetic strate-
gy is operationally simple, employs inexpen-
sive and readily available starting materials,
and proceeds under mild, easily controlled
reaction conditions, thus rendering it an ef-
ficient preparation of defactinib 2 either on a
laboratory or an industrial scale.
Avutometinib 3 (also known as VS-6766
or CH5126766) is an orally administered
dual RAF/MEK inhibitor distinguished by its
unique “RAF/MEK clamp” mechanism which
prevents MEK phosphorylation by RAF while
simultaneously inhibiting MEK kinase activity.
This dual action results in sustained suppres-
sion of ERK signaling, a pathway frequently
activated in RAS- and RAF-driven malignan-
cies. The compound was originally discovered
through collaborative efforts involving Japanese
and US research groups and was subsequent-
ly advanced clinically by Verastem Oncology.
Its development has focused on tumors char-
acterized by MAPK pathway dependence, par-
ticularly those harboring KRAS mutations [56].
The therapeutic rationale for avutometinib 3
aligns closely with the strategy described above
for defactinib 2, as the two agents were co-de-
veloped and clinically evaluated as a combina-
tion regimen. Avutometinib 3 has shown prom-
ise in treating low-grade, serous ovarian cancer
(LGSOC), a disease in which KRAS mutations
and MAPK pathway activation are common
and where standard therapies often only yield
limited benefits. The combination of avutom-
etinib 3 with defactinib 2 has also received US
FDA Orphan Drug Designation for metastat-
ic pancreatic cancer, reflecting its potential in
RAS-driven tumors. Additional areas of investi-
gation include endometrial cancer, NSCLC with
KRAS mutations, and other solid tumors exhib-
iting MAPK pathway dysregulation [62–64].
Avutometinib 3 is administered orally. In
the combination regimen with defactinib 2,
the clinically established dosing schedule con-
sists of a 3.2 mg dose twice weekly, typically
on days 1 and 4 of each 7-day period within a
28-day cycle. This intermittent schedule is de-
signed to optimize pathway suppression while
maintaining tolerability, a strategy supported
by pharmacodynamic studies demonstrating
prolonged ERK inhibition after each dose [65].
Preclinical studies show that avutometi
nib 3 produces sustained suppression of MEK
and ERK phosphorylation, induces apoptosis
in RAS-mutant cancer models, and enhanc-
es antitumor activity when combined with
FAK inhibition. Clinically, avutometinib 3 has
demonstrated meaningful activity in LGSOC,
including objective responses and durable di
sease control in patients previously treated with
multiple lines of therapy. In pancreatic cancer,
early-phase data from combination studies
with defactinib 2 and standard chemotherapy
have shown encouraging response rates and
reductions in tumor burden, supporting fur-
ther development [66].
In avutometinib 3, the CF3 group plays a
structural role that is closely tied to the drug’s
unusual mechanism as a dual RAF–MEK
“clamp” inhibitor. Rather than simply boost-
ing lipophilicity or metabolic stability, the CF3
group helps enforce a preferred three-dimen-
sional shape of the inhibitor, stabilizing the
conformation that allows simultaneous enga
gement of RAF and MEK. This conformation-
al steering is important because avutometinib
3 does not behave like classical MEK inhibi-
tors–it relies on a cooperative binding mode in
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which MEK is held in a catalytically inactive
state while remaining associated with RAF. The
CF3 group contributes to this by shifting the
electronic distribution of the heterocycle and
subtly altering torsional angles that favor the
clamp-competent geometry [63, 64].
Another consequence of the CF3 group is
its impact on the drug’s kinetic behavior. Avu-
tometinib 3 shows unusually durable suppres-
sion of ERK signaling despite intermittent do
sing. The CF3 group influences this by slowing
conformational relaxation and dissociation
from the RAF–MEK complex, which prolongs
target engagement even when plasma levels
begin to fall. This kinetic stabilization is a hall-
mark of many fluorinated kinase inhibitors,
but in avutometinib 3 it directly supports the
intermittent dosing schedule used clinically
[63–66]. Finally, the CF3 group helps balance
the molecule’s physicochemical properties so
that it can reach intracellular RAF–MEK as-
semblies without excessive polarity or rapid
clearance. In avutometinib 3, this balance is
less about maximizing permeability and more
about ensuring that the inhibitor maintains the
conformational rigidity and binding kinetics
required for its distinctive mechanism. This
fundamentally differs from how the CF3 group
in defactinib 2 impacts its attributes [62–66].
The synthesis of avutometinib 3 (Scheme 3),
as disclosed in a US Patent [67], begins with the
core building block 4-(bromomethyl)-3-fluoro-
2-nitropyridine (25). Nucleophilic substitution
of 25 with ethyl 3-oxobutanoate (26) in the
presence of NaH in tetrahydrofuran (THF) fur-
nishes the substituted keto-ester 27. Subsequent
condensation of 27 with resorcinol provides the
chromenone scaffold 29. Further elaboration
involves coupling 29 with 2-bromopyrimidine
30 under basic conditions to introduce the py-
rimidinol ester fragment, affording intermedi-
ate 31. Reduction of the nitro group in 31 then
yields the corresponding aniline 32. Finally,
acylation of the newly formed amino group
with methylsulfamoyl chloride delivers the tar-
get compound, avutometinib 3. Overall, the
sequence is concise, employs inexpensive rea-
gents, and is readily adaptable for scale up.
Scheme 3. Synthesis of avutometinib 3.
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ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
Imlunestrant (Inluriyo®) 4 is an orally ad-
ministered, next-generation selective estro-
gen receptor degrader (SERD) approved for
the treatment of adults with estrogen receptor
(ER)-positive, HER2-negative, ESR1-mutated
advanced, or metastatic breast cancer that has
progressed following at least one line of endo-
crine therapy. This patient population typical-
ly includes postmenopausal women, although
the indication formally applies to adults re-
gardless of sex [68].
Clinically, imlunestrant 4 addresses a ma-
jor mechanism of endocrine resistance: ESR1
ligand-binding domain mutations which stabi-
lize the receptor in an active conformation and
diminish the effectiveness of aromatase inhibi-
tors and earlier SERDs. Unlike fulvestrant–the
long-standing standard in this class–imlunes-
trant 4 is fully oral, exhibits high ER-binding
affinity, and induces efficient receptor degra-
dation across a broad spectrum of ESR1 mu-
tations. Its pharmacokinetic profile enables
consistent systemic exposure without the limi
tations of intramuscular administration [69].
Imlunestrant 4 has been evaluated both as
monotherapy and in combination with targe
ted agents such as CDK4/6 inhibitors, demon-
strating its role in modern endocrine-based
regimens for advanced breast cancer. The drug
represents a significant step forward in the
evolution of SERDs offering improved conveni-
ence, broader activity against resistance-associ-
ated ER variants, and a favorable safety profile
suitable for long-term outpatient therapy [70].
Imlunestrant 4 is administered orally once
daily, with or without food, using a fixed dos-
ing schedule designed to maintain continu-
ous estrogen receptor suppression suitable for
long-term outpatient therapy. The regimen is
compatible with combination strategies, in-
cluding co-administration with CDK4/6 in-
hibitors reflecting its integration into modern
endocrine-based treatment paradigms for ad-
vanced breast cancer [71].
Fluorine plays a strategically important role
in the biological performance of imlunest
rant 4. The drug contains multiple fluorine
substituents positioned to optimize both ER
binding and pharmacokinetic behavior, fea-
tures that distinguish it from earlier SERDs
such as fulvestrant. From a structural perspec-
tive, fluorine’s strong inductive effect and its
ability to modulate local conformational pre
ferences help stabilize the ligand in a bioactive
geometry that favors high-affinity engagement
with the ER ligand-binding domain, including
clinically relevant ESR1 mutations. These mu-
tations often shift the receptor toward a consti-
tutively active conformation, but the fluorina
ted scaffold of imlunestrant 4 maintains potent
antagonism and efficient receptor degradation
across these variants. Fluorination also contri
butes significantly to the drug’s metabolic sta-
bility. By blocking oxidative metabolism at key
positions, the fluorine atoms prolong syste
mic exposure and support the once-a-day oral
regimen, a major advantage over fulvestrant’s
intramuscular administration. Additionally,
fluorine fine tunes lipophilicity and membrane
permeability improving oral absorption and
ensuring adequate intracellular concentrations
for sustained ER degradation [68–71].
The practical synthesis of imlunestrant 4
(Scheme 4) was recently disclosed in a patent
application [72]. The sequence begins with
the addition of Grignard reagent 35 to the
carbonyl group of 3-chloro-7-methoxyquino
line-4-carbaldehyde (34) followed by MnO2
oxidation affording (3-chloro-7-methoxyquino
lin-4-yl)(4-fluorophenyl)methanone (36) in
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68% yield. Treatment of 36 with BBr3 in DCM
at low temperature effected demethylation of
the aromatic methoxy group to give the cor-
responding phenol 37. Nucleophilic substitu-
tion of 37 with 2-(3-(fluoromethyl)azetidine-
1-yl)ethanol (38) furnished ether 39, isolated
in 61% yield. Suzuki–Miyaura coupling of 39
with 4-(trifluoromethyl)phenylboronic acid
(40) introduced the second and final fluorina
ted aromatic fragment to yield biaryl inter-
mediate 41. Subsequent reduction of 41 with
LiBHEt3 produced alcohol 42 which cyclized
with NaH treatment in refluxing THF to gene
rate the target 43. Racemic imlunestrant 43 was
resolved into its enantiomers by supercritical
fluid chromatography (SFC). In this context,
it is worth noting the recently recognized con-
vergence between achiral simulated moving
bed chromatography and the self-dispropor-
tionation of enantiomers (SDE) phenomenon
[73–75] which potentially offers significant ad-
vantages for large-scale chiral separations.
Scheme 4. Synthesis of imlunestrant 4.
Ziftomenib (Komzifti©) 5, is a first-in-class,
orally bioavailable inhibitor of the menin–
KMT2A (MLL) protein–protein interaction, a
central epigenetic driver in leukemias charac-
terized by KMT2A rearrangements (KMT2A-r)
or NPM1 mutations. These AML subtypes
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ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
rely on menin-dependent transcriptional pro-
grams that maintain leukemic stemness and
block differentiation. By selectively disrupt-
ing the menin–KMT2A complex, ziftomenib
5 suppresses HOX/MEIS oncogenic signaling,
thereby promoting differentiation and apopto-
sis of leukemic blasts [76].
The compound was discovered and deve
loped by Kura Oncology, a company speciali
zing in precision oncology and epigenetic the
rapeutics. Following promising clinical acti
vity in heavily pre-treated patients, ziftomenib
(Komzifti©) received US FDA approval in
November 2025 for the treatment of relapsed
or refractory acute myeloid leukemia (AML)
with susceptible NPM1 mutations, addressing
a population with historically poor prognosis
and limited therapeutic options. Clinical re-
sponses include durable complete remissions
and measurable residual disease (MRD) ne
gativity. Combination regimens with veneto-
clax or hypomethylating agents are currently
under evaluation and may broaden its thera-
peutic utility [77].
From a medicinal chemistry standpoint,
ziftomenib 5 incorporates a strategically po-
sitioned fluorinated aromatic unit which con-
tributes to its high-binding affinity, optimized
physicochemical properties, and favorable
pharmacokinetic profile—hallmarks of mo
dern fluorine-enabled drug design. The mole-
cule demonstrates a refined selectivity profile
avoiding off-target interactions that limited
earlier generations of menin inhibitors [78].
Overall, ziftomenib 5 represents a significant
advance in targeted epigenetic therapy offering
a precision-guided treatment option for geneti-
cally defined AML subsets and exemplifying the
sophisticated use of fluorine in contemporary
anticancer drug development [76–79].
The synthesis of ziftomenib 5 (Scheme 5)
has been disclosed in two US patents [80, 81]
and begins with the activation of 2-amino-
5 - ( 2 , 2 , 2 - t r i f lu oro e t hy l ) t h i oph e n e - 3 -
carboxamide (44) using bis(trichloromethyl)
carbonate (BTC) to afford bicyclic intermedi-
ate 45. Subsequent treatment of 6-(2,2,2-tri-
fluoroethyl)thieno[2,3-d]pyrimidine-2,4-diol
(45) with PCl5 exchanges the aromatic hy-
droxy group for a chloro substituent to yield
compound 46. Nucleophilic substitution of
this chlorine atom with t-butyl 4-aminopip-
eridine-1-carboxylate (47) furnishes inter-
mediate 48 and displacement of the second
chlorine with methylamine in refluxing etha-
nol provides compound 49. Boc-deprotection
with TFA then yields the corresponding di-
amine 50. The resulting fragment undergoes
reductive amination with the (S)-indole de-
rivative 51 in the presence of triethylamine
and NaBH(OAc)3 to give the protected in-
dole–piperazine conjugate 52. Subsequent
Boc removal with excess TFA affords the free
indole–piperazine amine 53. Finally, mesyla-
tion with methanesulfonyl chloride and tri-
ethylamine furnishes ziftomenib 5.
Datopotamab deruxtecan 6, is a next-gene
ration TROP2-targeted ADC designed to
deliver a highly potent topoisomerase I in-
hibitor (DXd) selectively to tumor cells. The
agent consists of a humanized IgG1 monoclo-
nal antibody against TROP2 conjugated via
a cleavable tetrapeptide linker to the exate-
can-derived DXd payload. Upon binding to
TROP2 on the tumor cell surface, the ADC is
internalized and trafficked to lysosomes where
enzymatic cleavage releases DXd inducing
DNA double-strand breaks and apoptosis in
TROP2-expressing cancer cells [82].
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Scheme 5. Synthesis of ziftomenib 5.
Clinically, datopotamab deruxtecan 6 has
demonstrated significant antitumor activity
in hormone receptor-positive, HER2-negative
metastatic breast cancer, and in EGFR-mu-
tated NSCLC previously treated with targeted
therapy and platinum chemotherapy. The drug
received US FDA approval in January 2025 for
unresectable or metastatic HR+/HER2− breast
cancer with expanded approval in June 2025
for EGFR-mutated NSCLC. It was also ap-
proved in the EU (April 2025) and Japan (De-
cember 2024) for similar indications [83].
Pharmacologically, datopotamab deruxte-
can 6 employs an optimized drug-to-antibody
ratio of 4 balancing payload potency with sys-
temic tolerability. The DXd payload is more
potent than SN-38, the payload used in sacitu-
zumab govitecan, and the linker is engineered
for high plasma stability with tumor-selective
cleavage. The agent is administered intrave-
nously at 6 mg/kg every 3 weeks until progres-
sion or unacceptable toxicity occurs [84].
The safety profile is consistent with the
DXd-ADC class, with notable risks including
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ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
interstitial lung disease/pneumonitis, ocular
toxicities (e.g., dry eye, keratitis), stomatitis,
nausea, fatigue, and myelosuppression. Careful
monitoring for respiratory and ocular symp-
toms is required and dose modifications are
recommended based on severity [85].
Although datopotamab deruxtecan 6 is
structurally defined by its ADC architecture,
the critical fluorine element resides within
the DXd payload, an exatecan-derived topo
isomerase I inhibitor. Fluorination plays a cen-
tral role in shaping the pharmacological per-
formance of the payload and, consequently, the
therapeutic index of the entire ADC [86].
From a chemical perspective, fluorine en-
hances the metabolic stability of the DXd scaf-
fold, reducing susceptibility to oxidative degra-
dation, and prolonging the intracellular persis-
tence of the active species following lysosomal
release. This increased stability contributes
directly to the high cytotoxic potency charac-
teristic of DXd-based ADCs. Fluorination also
modulates the lipophilicity and membrane
permeability of the payload enabling efficient
intracellular diffusion while maintaining a
controlled bystander effect–an essential ba
lance for ADCs targeting heterogeneously ex-
pressed antigens such as TROP2 [82, 85].
Electronically, the presence of fluorine fine
tunes the pharmacophore, improving binding
affinity to topoisomerase I and stabilizing the
ternary drug–enzyme–DNA cleavage com-
plex. These effects underpin the superior po-
tency of DXd relative to earlier camptothecin
analogs such as SN-38. In addition, the fluo
rinated structure contributes to the chemical
robustness of the payload–linker system sup-
porting high plasma stability and minimizing
premature drug release. Collectively, these
fluorine-driven properties enable datopotamab
deruxtecan 6 to achieve potent, selective, and
clinically meaningful antitumor activity while
preserving an acceptable safety profile [83–86].
Overall, datopotamab deruxtecan 6 represents
an important advancement in TROP2-directed
therapy offering a potent and clinically valida
ted option for patients with heavily pre-treated
breast cancer and EGFR-mutated NSCLC.
The fluorine-containing component of
datopotamab deruxtecan 6 is exatecan 64
(Scheme 6) [87, 88]. Its synthesis begins from
2-fluoro-1-methyl-4-nitrobenzene 54 which
undergoes bromination with N-bromosucci
nimide in sulfuric acid–heptane followed by
platinum-catalyzed hydrogenation of the nitro
group in EtOAc to afford the corresponding
aniline. Acetylation with acetic anhydride and
triethylamine furnishes the brominated ani-
lide 55. This aryl bromide then participates in
a palladium-catalyzed C–C coupling with but-
3-enoic acid (56) in the presence of DIPEA
yielding an alkene intermediate that is subse-
quently hydrogenated in 2-Me-THF to provide
the saturated acid 57.
Activation of the carboxylic acid with TFA
promotes an intramolecular Friedel–Crafts
acylation producing the tetrahydronaphthale-
none 58. Nitration at the α position of the ke-
tone is achieved using amyl nitrite and potas-
sium t-butoxide in THF; catalytic hydrogena-
tion of the resulting nitro group then provides
the corresponding primary amine followed by
acetylation with Ac2O in acetic acid to afford
compound 59. Selective deacetylation of the
anilide—leaving the aliphatic amide intact–is
accomplished by heating with hydrochloric
acid in ethanol yielding amine 60. Condensa-
tion of 60 with ketone 61 in o-cresol–toluene
with catalytic amounts of pyridinium p-tolue-
nesulfonate (PPTS) forms enamine 62 which
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undergoes dehydrative cyclization to quinoline
63. Treatment with aqueous methanesulfonic
acid in ethyl cyclohexene–2-methoxyethanol
affords the mesylate salt of exatecan dihydrate
64, along with the epi-exatecan diastereomer.
The latter is recycled through an amine protec-
tion–deprotection–crystallization sequence to
complete the synthesis [87, 88].
Scheme 6. Synthesis of exatecan 64, the fluorine-containing component
of datopotamab deruxtecan 6.
Taletrectinib (Ibtrozi©) 7 is an orally admi
nistered, next-generation selective inhibitor of
ROS1 and NTRK fusion kinases approved for
adults with ROS1-positive metastatic NSCLC,
including patients previously treated with
first-generation ROS1 inhibitors such as crizo-
tinib. The drug was designed to overcome the
two major limitations of earlier ROS1-targeted
therapies: poor CNS penetration and vulnera
bility to resistance-conferring kinase-domain
mutations, particularly the solvent-front mu-
tation G2032R which is a common mechanism
of acquired resistance to crizotinib and en-
trectinib. Taletrectinib 7 exhibits high potency
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across a broad spectrum of ROS1 alterations,
including clinically relevant resistance muta-
tions, and demonstrates robust intracranial ac-
tivity, an essential feature given the high inci-
dence of brain metastases in ROS1-rearranged
NSCLC [89–91].
Compared with existing ROS1 inhibitors,
taletrectinib 7 offers a more mutation-agnostic
profile, improved CNS exposure, and a favora-
ble tolerability pattern with reduced off-target
TRK-related adverse effects. Its activity in both
TKI-naïve and TKI-experienced patients posi-
tions represents a meaningful advancement in
the management of ROS1-driven lung cancer,
particularly for individuals whose disease has
progressed on from earlier generation agents.
The approved indication applies to adults of
all ages, though the typical patient population
skews toward younger non-smokers, reflecting
the epidemiology of ROS1-rearranged NSCLC
[92, 93].
Taletrectinib 7 is administered orally once
daily using a fixed dosing regimen suitable for
long-term outpatient therapy. The drug’s fluo-
rine-containing structural elements contribute
to its kinase-binding affinity, metabolic stabi
lity, and CNS penetration–properties central to
its clinical performance. Overall, taletrectinib
7 represents a significant step forward in pre-
cision oncology for ROS1-positive lung cancer
offering durable systemic and intracranial re-
sponses in a population with limited targeted
options after resistance emerges [93].
The synthesis of taletrectinib (7) (Scheme 7)
is described in patent literature [94, 95] and fol-
lows a convergent route centered on late-stage
Suzuki–Miyaura cross-coupling. The sequence
begins with a Mitsunobu reaction between
the chiral amine 65 and derivative 66. This
reaction is typically performed using triphe-
nylphosphine (PPh₃) and diisopropyl azodi-
carboxylate (DIAD) in anhydrous tetrahydro-
furan (THF) at 0 °C to room temperature for
12–24 hours. The Mitsunobu coupling pro-
ceeds with clean stereochemical inversion, fur-
nishing the corresponding adduct 67 in good
yield (typically 70–85% after purification by
column chromatography or recrystallization).
This intermediate 67 then undergoes Suzuki–
Miyaura cross-coupling with boronic acid 68.
The reaction is commonly carried out us-
ing a palladium catalyst such as Pd(OAc)₂ or
PdCl₂(dppf)·CH₂Cl₂ (2–5 mol%), in the pres-
ence of a base like K₃PO₄ or potassium car-
bonate, in a mixed solvent system such as
DMAc/water or dioxane/water at 80–100 °C
for 4–12 hours under inert atmosphere. These
conditions afford the Boc-protected biaryl
amine 69 in high yield (80–94% after aqueous
workup and crystallization). Finally, Boc de-
protection of intermediate 69 is achieved un-
der acidic conditions, most commonly using 4
M HCl in 1,4-dioxane or HCl in dichlorometh-
ane/methanol at room temperature to 75 °C
for 2–6 hours. This step delivers taletrectinib
(7) as the free base in excellent yield (typically
85–95%). The free base can be further conver
ted to the pharmaceutically preferred adipate
salt by treatment with adipic acid in a suitable
solvent (e.g., ethanol or isopropanol) followed
by crystallization, often providing the final API
in >90% yield and high purity. This synthetic
route is relatively concise (3–4 linear steps from
key building blocks), scalable, and features ro-
bust palladium-catalyzed coupling as the key
bond-forming step. Purification at each stage
is typically achieved through crystallization
rather than extensive chromatography in opti
mized process versions, supporting its use in
clinical and commercial manufacture.
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Scheme 7. Synthesis of taletrectinib 7.
CONCLUSIONS. This review highlights
seven fluorine-containing oncology therapeu-
tics that received US FDA approval in 2025.
Sunvozertinib (Zegfrovy©) 1 was approved
for adults with locally advanced or metastatic
NSCLC. The co‑approved oral regimen of de-
factinib 2 and avutometinib (Avmapki©) 3 is
indicated for adults with KRAS-mutated recur-
rent low-grade serous ovarian cancer following
prior systemic therapy. Imlunestrant (Inlu
riyo©) 4 received approval for the treatment
of estrogen receptor-positive, HER2-negative,
ESR1-mutated advanced or metastatic breast
cancer that has progressed after at least one line
of endocrine therapy. Ziftomenib (Komzifti©)
5 was approved for adults with relapsed or
refractory acute myeloid leukemia harboring
susceptible NPM1 mutations. Datopotamab
deruxtecan (Datroway©) 6, a TROP2-directed
ADC, was authorized for unresectable or meta
static hormone receptor-positive, HER2-nega-
tive breast cancer after endocrine therapy and
chemotherapy, as well as for certain adults
with previously treated advanced NSCLC. Fi-
nally, taletrectinib (Ibtrozi©) 7 was approved
for adults with locally advanced or metasta
tic ROS1-positive NSCLC, including both
TKI-naïve and TKI-experienced patients.
As discussed, fluorine plays a central role
in shaping the pharmacological performance
of all seven agents profiled in this review. Stra-
tegic fluorination is used throughout these
molecules to fine tune electronic properties,
enhance target binding, and improve physico-
chemical behavior essential for clinical success.
Incorporation of fluorine often increases me
tabolic stability by blocking oxidative hotspots,
thereby prolonging systemic exposure and ena-
bling once-daily oral dosing for several of these
therapies. Fluorine substitution also modulates
lipophilicity and membrane permeability, con-
tributing to improved tissue distribution and,
in some cases, enhanced CNS penetration, as
exemplified by taletrectinib 7. In kinase inhi
bitors such as sunvozertinib 1, avutometinib 3,
and imlunestrant 4, fluorinated motifs help
optimize potency, selectivity, and conforma-
tional control within ATP-binding pockets.
For complex modalities like the ADC dato-
potamab deruxtecan 6, fluorine contributes to
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ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
the stability and performance of both the pay-
load and linker system. Across these diverse
therapeutic classes, fluorine consistently serves
as a powerful design element that enables me-
dicinal chemists to balance potency, safety, and
pharmacokinetics—ultimately supporting the
successful translation of these compounds into
effective anticancer medicines.
A further unifying feature of these agents is
their chirality: five of the seven drugs are chiral
and are administered exclusively enantiopure.
In accordance with US FDA expectations for
chiral pharmaceuticals [96–98], the continued
development of robust asymmetric synthe
tic methods and advanced analytical tools for
fluorine-containing chiral molecules remains
essential. Particular attention should be gi
ven to the SDE phenomenon which can occur
under various physicochemical conditions for
enantioenriched samples [99–102]. SDE is es-
pecially relevant for chiral drugs incorporating
fluorinated motifs [103–105] and/or amino
acid-derived fragments [106–108] as these
structural elements can amplify the propensity
for enantiomeric redistribution. Because such
behavior poses a tangible public safety concern,
rigorous assessment of enantiomeric purity is
required throughout the entire drug lifecycle
[109–112]. Continuous monitoring of stereo-
chemical integrity during synthesis [113,114],
manufacturing, and even long-term storage is
critical, particularly since sublimation-driven
SDE has been documented as a specific chal-
lenge for fluorine-containing pharmaceuticals
[115–118].
Growing public concern about the poten-
tial health risks associated with certain fluo-
rine-containing substances, particularly per-
sistent per- and polyfluoroalkyl substances
(PFAS), warrants careful consideration [119–
122]. While most organofluorine pharmaceu-
ticals exhibit minimal defluorination and do
not significantly contribute to inorganic fluo-
ride burden [123], patients on long-term fluo
rinated medications may wish to discuss total
fluoride exposure with their physicians when
appropriate, including from sources such as
fluoridated water and foods produced with
fluorinated agrochemicals [124]. The broader
environmental and health impacts of persis-
tent perfluorinated “forever chemicals” (PFAS)
[125], alongside other modern pollutants such
as bioavailable plastics [126], underscore the
need for continued vigilance and responsible
management of fluorinated substances across
industrial, agricultural, and pharmaceutical
applications.
Despite these issues, the essential role of
pharmaceuticals in modern medicine remains
unquestionable. These agents provide life-sa
ving interventions, enhance quality of life
across countless conditions, and continue to
drive therapeutic innovation. Their develop-
ment not only addresses urgent medical needs
but also lays the groundwork for future ad-
vances in healthcare.
AUTHORS’ CONTRIBUTION. All authors
have read the research results and approved
the final version of the manuscript.
CONFLICT OF INTEREST. The authors de-
clare no conflict of interest.
ACKNOWLEDGMENTS. We acknow
ledge the financial support from
IKERBASQUE, Basque Foundation for
Science (for Soloshonok). The authors
acknowledge the assistance of Microsoft
Copilot and Google Gemini for their
support in translating to Ukrainian.
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ХІМІЯ ФТОРОРГАНІЧНИХ СПОЛУК В ОНКОЛОГІЇ:
ОГЛЯД ПРОТИПУХЛИННИХ ПРЕПАРАТІВ,
СХВАЛЕНИХ FDA США У 2025 РОЦІ (ОГЛЯД)
Аліція Взорек¹, Тайзо Оно2,
Карел Д. Кліка3, Наталія B. Лютенко4,
Вадим А. Солошонoк5
1 Хімічний інститут, Університет Яна
Кохановського в Кельці,
вул. Університетська 7, 25-406 Кельце,
Польща;
2 Національний інститут передової науки
та технологій (AIST),
2266-98, Анагахора, Шімошідамі, район
Моріяма, Нагоя, 463-8560, Японія;
3 Гамбурзький передовий дослідницький
центр біоорганічної хімії (HARBOR),
Університет Гамбурга, Luruper Chaussee
149, 22761 Гамбург, Німеччина;
4 Інститут біоорганічної хімії та
нафтохімії ім. В. П. Кухаря НАН України,
вул. Академіка Кухаря, 1, Київ 02094,
Україна;
5 ІКЕРБАСКЕ, Баскська наукова фундація,
вул. Марія Діас де Харо 3, Площа Бізкая,
48013 Більбао, Іспанія
e-mail: vadimsoloshonok@gmail.com
У 2025 році Управління з продовольства
та медикаментів США (FDA) схвалило сім
протиракових препаратів, які містять фтор,
що відображає продовження впливу стра-
тегій фторування в сучасному дизайні он-
кологічних лікарських засобів. Ці новосхва-
лені терапії охоплюють широкий спектр
злоякісних новоутворень і механізмів дії.
Сунвозертиніб (Zegfrovy©) було схвалено
для лікування місцево-поширеного або ме-
тастатичного недрібноклітинного раку ле-
гень (НДКРЛ). Комбінація дефактінібу та
авуметинібу (Avmapki©) пропонує таргетну
опцію для KRAS-мутованого рецидивно-
го низькосортного серозного раку яєчни-
ків. Імлунестрант (Inluriyo©) є препаратом
наступного покоління ендокринної тера-
пії для естроген-рецептор-позитивного,
HER2-негативного, ESR1-мутованого по-
ширеного раку молочної залози. Зіфтоме-
ніб (Komzifti©) представляє прецизійну те-
рапію для рецидивного або рефрактерного
гострого мієлоїдного лейкозу з чутливими
мутаціями NPM1. Датопотамаб деруксте-
кан (Datroway©) – це спрямований на TROP2
антитіло-лікарський кон’югат, який роз-
ширює можливості лікування гормон-ре-
цептор-позитивного, HER2-негативного
метастатичного раку молочної залози та
окремих груп пацієнтів із раніше лікова-
ним НДКРЛ. Талетректиніб (Ibtrozi©) – ін-
гібітор ROS1 наступного покоління – було
схвалено для лікування ROS1-позитивного
НДКРЛ як у TKI-наївних, так і в TKI-дос-
відчених пацієнтів. У сукупності ці аген-
ти демонструють універсальність фтору в
підвищенні потужності, селективності та
фармакокінетичних властивостей у різних
терапевтичних модальностях.
Для кожної розглянутої сполуки ми на-
даємо комплексне обговорення її відкрит-
тя, біологічного механізму дії, терапевтич-
ного застосування, клінічного введення,
ролі фторування в оптимізації її власти-
востей, а також детальний опис хімічного
синтезу.
Ключові слова: фтор, дизайн лікарських
засобів, онкологія, синтез, хіральність,
фармакологія, терапевтика.
72 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
REFERENCES
1. Mohammed M.A., Moles R.J., Chen T.F. Im-
pact of Pharmaceutical Care Interventions
on Health-Related Quality-of-Life Outcomes:
A Systematic Review and Meta-analysis. Ann.
Pharmacother. 2016. 50(10): 862–881.
https://doi.org/10.1177/1060028016656016.
2. Lichtenberg F.R., Virabhak S. Pharmaceutical‐
embodied technical progress, longevity, and
quality of life: drugs as ‘Equipment for Your
Health’. Manag. Decis. Econ. 2007 28(4–5):
371–392. https://doi.org/10.1002/mde.1347.
3. Cook M.A., Wright G.D. The past, present,
and future of antibiotics. Sci. Transl. Med.
2022. 14(657): 7793.
https://doi.org/10.1126/scitranslmed.abo77.
4. Barot S., Patel H., Yadav A., Ban I. Recent
advancement in targeted therapy and role of
emerging technologies to treat cancer. Med.
Oncol. 2023. 40(11): 324.
https://doi.org/10.1007/s12032-023-02184-6.
5. Zuvekas S.H. Prescription drugs and the
changing patterns of treatment for mental dis-
orders, 1996–2001. Health Affairs. 2005. 24(1):
195–205.
https://doi.org/10.1377/hlthaff.24.1.195.
6. Lee E.K., Maheshwary S., Mason J., Glisson W.
Decision support system for mass dispensing
of medications for infectious disease outbreaks
and bioterrorist attacks. Ann. Oper. Res. 2006.
148: 25–53.
https://doi.org/10.1007/s10479-006-0087-7.
7. Wang J., Sánchez-Roselló M., Aceña J.L. et al.
Fluorine in pharmaceutical industry: fluo-
rine-containing drugs introduced to the mar-
ket in the last decade (2001–2011). Chem. Rev.
2014. 114(4): 2432–2506.
https://doi.org/10.1021/cr4002879.
8. Shah P., Westwell A.D. The role of fluorine in
medicinal chemistry. J. Enzyme Inhib. Med.
Chem. 2007. 22(5): 527–540.
https://doi.org/10.1080/14756360701425014.
9. Swallow S. Fluorine in medicinal chemistry.
Prog. Med. Chem. 2015. 54: 65–133.
https://doi.org/10.1016/bs.pmch.2014.11.001.
10. Filler R., Saha R. Fluorine in medicinal che
mistry: a century of progress and a 60-year ret-
rospective of selected highlights. Future Med.
Chem. 2009. 1(5): 777–791.
https://doi.org/10.4155/fmc.09.65.
11. O’Hagan D., Young R.J. Future challenges and
opportunities with fluorine in drugs? Med.
Chem. Res. 2023. 32(7): 1231–1234.
https://doi.org/10.1007/s00044-023-03094-y.
12. O’Hagan D. Fluorine in health care: Organo-
fluorine containing blockbuster drugs. J. Fluor.
Chem. 2010. 131(11): 1071–1081.
https://doi.org/10.1016/j.jfluchem.2010.03.
003.
13. Han J., Remete A.M., Dobson L.S. et al. Next
generation organofluorine containing block-
buster drugs. J. Fluor. Chem. 2020. 239: 109639.
https://doi.org/10.1016/j.jfluchem.2020.1096
39.
14. Soloshonok V.A., Mikami K., Yamazaki T.,
Welch J.T., Honek J.F. (Eds.). Current Fluoro-
organic Chemistry: New Synthetic Directions,
Technologies, Materials, and Biological Appli-
cations. ACS Symposium Series, Vol. 949. Ox-
ford University Press, New York, 2007.
https://doi:10.1021/bk-2007-0949.
15. Han J., Wzorek A., Dhawan G. et al. Chiral,
fluorine-containing pharmaceuticals, Ukr.
Chem. J. 2025. 91(2): 55–90.
https://doi.org/10.33609/2708-129X.91.2.
2025.55-90.
16. Zhou Y., Wang J., Gu Z. et al. Next Genera-
tion of Fluorine-Containing Pharmaceuticals,
Compounds Currently in Phase II–III Clinical
Trials of Major Pharmaceutical Companies:
New Structural Trends and Therapeutic Areas.
Chem. Rev. 2016. 116(2): 422–518.
https://pubs.acs.org/doi/10.1021/acs.chem-
rev.5b00392
17. Mei H., Han J., Fustero S. et al. Fluorine‐Con-
taining Drugs Approved by the FDA in 2018.
Chem.—Eur. J. 2019. 25(51): 11797–11819.
https://doi.org/10.1002/chem.201901840.
18. Mei H., Remete A.M., Zou Y. et al. Fluorine-
containing drugs approved by the FDA in
2019. Chin. Chem. Lett. 2020. 31(9): 2401–2413.
https://doi.org/10.1016/j.cclet.2020.03.050.
19. Wang Q., Bian Y., Dhawan G. et al. FDA ap-
proved fluorine-containing drugs in 2023.
Chin. Chem. Lett. 2024. 35(11): 109780.
https://doi.org/10.1016/j.cclet.2024.109780.
20. Yu Y., Liu A., Dhawan G. et al. Fluorine-con-
taining pharmaceuticals approved by the FDA
73https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Karel D. Klika, Nataliya V. Lyutenko, Vadim A. Soloshonok UCJ № 4/ Vol. 92
in 2020: Synthesis and biological activity. Chin.
Chem. Lett. 2021. 32(11): 3342–3354.
https://doi.org/10.1016/j.cclet.2021.05.042.
21. He J., Li Z., Dhawan G. et al. Fluorine-contai
ning drugs approved by the FDA in 2021.
Chin. Chem. Lett. 2023. 34(1): 107578.
https://doi.org/10.1016/j.cclet.2022.06.001.
22. Du Y., Bian Y., Baecker D. et al. Fluorine in
the Pharmaceutical Industry: FDA‐Approved
Fluorine‐Containing Drugs in 2024. Chem.—
Eur. J. 2025. e202500662.
https://doi.org/10.1002/chem.202500662.
23. Lyutenko N.V., Han J., Wzorek A. et al. Car-
bon nanotubes-catalyzed synthesis of fluo-
rine-containing heterocycles, Ukr. Chem. J.
2024. 90(6): 71–86.
https://doi.org/10.33609/2708-129X.90.6.
2024.71-86.
24. Han J., Wzorek A., Ono T. et al. Mechano-
chemical Synthesis of Fluorine-Containing
Heterocycles via Ball Milling. Ukr. Chem. J.
2025. 91(7), 35–55.
https://doi.org/10.33609/2708-129X.91.7.
2025.35-55.
25. Wzorek A., Ono T., Baecker D. et al. Elec-
trochemical Synthesis of Fluorinated Hete
rocyclic Compounds. Ukr. Chem. J. 2025.
91(11): 35–62. https://doi.org/10.33609/2708-
129X.91.11.2025.35-62.
26. Wzorek A., Ono T., Baecker D. et al. Recent
Advances in Photochemical Approaches for
the Preparation of Fluorine-Containing He
terocycles. Ukr. Chem. J. 2026. 92(2), 26–82.
https://doi:10.33609/2708-129X.92.2.2026.
26-82.
27. Xu J., Liu J., Mei H. et al. A three-component
cycloaddition of alkyl trifluorodiazoethane for
the synthesis of trifluoromethylated isoxazo-
lines. Chem. Het. Comp. 2023. 59(6): 465–71.
https://doi.org/10.1007/s10593-023-03217-8.
28. Rizzo C., Amata S., Pibiri I. et al. FDA-ap-
proved fluorinated heterocyclic drugs from
2016 to 2022. Int. J. Mol. Sci. 2023. 24(9): 7728.
https://doi.org/10.3390/ijms24097728.
29. He J., Wang C., Mei H. et al. Visible-light-pro-
moted cyclization of 3-indolylallylamides ena
bling synthesis of tetrahydrocarbolinones. Tet-
rahedron. 2024. 150: 133776.
https://doi.org/10.1016/j.tet.2023.133776.
30. Abbas A.A., Farghaly T.A., Dawood K.M. Re-
cent progress in therapeutic applications of
fluorinated five-membered heterocycles and
their benzo-fused systems. RSC Adv. 2024.
14(46): 33864–33905.
https://doi:10.1039/D4RA05697C.
31. Yamada T., Okada T., Sakaguchi K. et al. Effi-
cient asymmetric synthesis of novel 4-substi-
tuted and configurationally stable analogues of
thalidomide. Org. Lett. 2006. 8(24): 5625–5628.
https://doi:10.1021/ol0623668.
32. Wang Q., Han J., Sorochinsky A. et al. The La
test FDA-Approved Pharmaceuticals Contain-
ing Fragments of Tailor-Made Amino Acids
and Fluorine. Pharmaceuticals. 2022. 15(8):
999.
https://doi.org/10.3390/ph150809991847558.
33. Han J., Wzorek A. Dhawan G. et al. New drugs
on the pharmaceutical market containing fluo
rine and residues of tailor-made amino acids.
Ukr. Chem. J. 2024. 90(9): 31–56.
https://doi:10.33609/2708-129X.90.9.2024.
31-56.
34. Yin Z., Hu W., Zhang W. et al. Tailor-made
amino acid-derived pharmaceuticals approved
by the FDA in 2019. Amino Acids. 2020. 52(9):
1227–1261.
https://doi:10.1007/s00726-020-02887-4.
35. Mei H., Han J., White S. et al. Tailor-made ami-
no acids and fluorinated motifs as prominent
traits in modern pharmaceuticals. Chem.–Eur.
J. 2020. 26(50): 11349–11390.
https://doi:10.1002/chem.202000617.
36. Ellis T.K., Hochla V.M., Soloshonok V.A. Effi-
cient synthesis of 2-aminoindane-2-carboxylic
acid via dialkylation of nucleophilic glycine
equivalent. J. Org. Chem. 2003. 68(12): 4973–
4976.
https://doi.org/10.1021/jo030065v.
37. Han J., Konno H., Sato T. et al. Peptidomi-
metics and Peptide-Based Blockbuster Drugs.
Curr. Org. Chem. 2021. 25(14): 1627–1658.
https://doi:10.2174/138527282566621061015
5047.
38. Han J., Konno H., Sato T. et al. Tailor-made
amino acids in the design of small-molecule
blockbuster drugs. Eur. J. Med. Chem. 2021.
220: 113448.
https://doi:10.1016/j.ejmech.2021.113448.
74 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
39. Liu A., Han J., Nakano A. et al. New pharma-
ceuticals approved by FDA in 2020: Small-
molecule drugs derived from amino acids and
related compounds. Chirality. 2022. 34(1):
86–103.
https://doi:10.1002/chir.23376.
40. Wang N., Mei H., Dhawan G. et al. New Ap-
proved Drugs Appearing in the Pharmaceu-
tical Market in 2022, Featuring Fragments of
Tailor-Made Amino Acids and Fluorine. Mo
lecules. 2023. 28(9): 3651.
https://doi:10.3390/molecules28093651.
41. Han J., Wzorek A., Dhawan G. et al. New
drugs appearing on the market in 2023: mole-
cules containing fluorine and fragments of tai-
lor-made amino acids. Ukr. Bioorg. Acta. 2024.
19(1): 3–20.
https://doi:10.15407/bioorganica2024.01.003.
42. Hutt A.J., Tan S.C. Drug Chirality and its Clini
cal Significance. Drugs. 1996. 52(5): 1–12.
https://doi.org/10.2165/00003495-199600525-
00003.
43. Lin G.Q., You Q.D., Cheng J.F. Chiral drugs. In:
Chemistry and Biological Action. Wiley, 2011.
https://doi:10.1002/9781118075647.
44. Brooks W.H., Guida W.C., Daniel K.G. The
significance of chirality in drug design and de-
velopment. Curr. Top. Med. Chem. 2011. 11(7):
760–770.
https://doi:10.2174/156802611795165098.
45. Ceramella J., Iacopetta D., Franchini A. et al.
A look at the importance of chirality in drug
activity: Some significative examples. Appl.
Sci. 2022. 12(21): 10909.
https://doi.org/10.3390/app122110909.
46. Calcaterra A., D’Acquarica I. The market of
chiral drugs: Chiral switches versus de novo
enantiomerically pure compounds. J. Pharm.
Biomed. Anal. 2018. 147: 323–340.
https://doi.org/10.1016/j.jpba.2017.07.008.
47. Wang M., Yang J.C., Mitchell P.L. et al. Sun-
vozertinib, a selective EGFR inhibitor for pre-
viously treated non-small cell lung cancer with
EGFR exon 20 insertion mutations. Cancer
Discov. 2022. 12(7): 1676–1689.
https://doi:10.1158/2159-8290.CD-21-1615.
48. Wang M., Fan Y., Sun M. et al. Sunvozertinib
for patients in China with platinum-pretreated
locally advanced or metastatic non-small-cell
lung cancer and EGFR exon 20 insertion mu-
tation (WU-KONG6): single-arm, open-label,
multicentre, phase 2 trial. Lancet Respir. Med.
2024. 12(3): 217–124.
https://doi:10.1016/S2213-2600(23)00379-X.
49. Yang J.C., Wang M., Doucet L. et al. Phase II
dose-randomized study of sunvozertinib in
platinum-pretreated non-small cell lung can-
cer with epidermal growth factor receptor
exon 20 insertion mutations (WU-KONG1B).
J. Clin. Oncol. 2025. 43(29): 3198–3208.
https://doi:10.1200/JCO-25-00788.
50. Mitsudomi T. Sunvozertinib: shining light on
lung cancer’s exon 20 fight. Transl. Lung Can-
cer Res. 2025. 14(2): 334–340.
https://doi:10.21037/tlcr-24-907.
51. Kumbhare M., Gadekar D., Chandak S., Man-
kar S. Sunvozertinib A Next-Generation EGFR
Exon 20 Insertion Inhibitor Transforming
NSCLC Therapy. Chin. J. App. Physiol. 2026.
42: e20260005.
https://doi:10.62958/j.cjap.2026.005.
52. Wang Y.T., Yang P.C., Zhang J.Y., Sun J.F. Syn-
thetic routes and clinical application of repre-
sentative small-molecule EGFR inhibitors for
cancer therapy. Molecules. 2024. 29(7): 1448.
https://doi.org/10.3390/molecules29071448.
53. Wang M, Fan Y, Sun M, Wang Y, Zhao Y,
Jin B, Hu Y, Han Z, Song X, Liu A, Tang K.
Sunvozertinib for patients in China with plati-
num-pretreated locally advanced or metastat-
ic non-small-cell lung cancer and EGFR exon
20 insertion mutation (WU-KONG6): sin-
gle-arm, open-label, multicentre, phase 2 trial.
The Lancet Respiratory Medicine. 2024 Mar 1.
12(3): 217–224.
https://doi.org/10.1016/S2213-2600(23)004
43-3.
54. Moore J.L., Taylor S.M., Soloshonok V.A. An
efficient and operationally convenient general
synthesis of tertiary amines by direct alkyla
tion of secondary amines with alkyl halides in
the presence of Huenig’s base. Arkivoc. 2005.
6(iv): 287–292.
https://doi.org/10.3998/ark.5550190.0006.624.
55. Capelletto E., Bironzo P., Denis L. et al. Single
agent VS-6766 or VS-6766 plus defactinib in
KRAS-mutant non-small-cell lung cancer: the
RAMP-202 phase II trial. Future Oncol. 2022.
75https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Karel D. Klika, Nataliya V. Lyutenko, Vadim A. Soloshonok UCJ № 4/ Vol. 92
18(16): 1907–1915.
https://doi.org/10.2217/fon-2021-1582.
56. Blair H.A. Avutometinib and Defactinib: First
Approval: Drugs. 2025. 85(10): 1319–1327.
https://doi.org/10.1007/s40265-025-02215-8.
57. Abbas M., Sami S.H., Gajdács M., Tariq M.J. Re-
cent FDA-approved kinase inhibitors for cancer
therapy in 2025: A comprehensive review and
perspectives. EXCLI J. 2025. 24: 1609.
https://doi:10.17179/excli2025-8972.
58. Wan Z., Zhu Z., Wang P. et al. Targeting fo-
cal adhesion kinase in lung diseases: current
progress and future directions. Biomolecules.
2025. 15(9): 1233.
https://doi.org/10.3390/biom15091233.
59. Geijerman E., Terrana F., Peters G.J. et al. Tar-
geting a key FAK-tor: the therapeutic potential
of combining focal adhesion kinase (FAK) in-
hibitors and chemotherapy for chemoresistant
non-small cell lung cancer. Expert Opin. Inves-
tig. Drugs. 2024. 33(11): 1103–1118.
https://doi.org/10.1080/13543784.2024.24177
62.
60. Hu H.H., Wang S.Q., Shang H.L. et al. Roles
and inhibitors of FAK in cancer: current ad-
vances and future directions. Front. Pharma-
col. 2024. 15: 1274209.
https://doi:10.3389/fphar.2024.1274209.
61. Aakriti J., Vithalkar M.P., Maity S. et al. Focal
adhesion kinase (FAK): emerging target for
drug-resistant malignant tumors. Mol. Biol.
Rep. 2025. 52(1): 248.
https://doi.org/10.1007/s11033-025-10296-7.
62. Kelliher L., Yoeli-Bik R., Schweizer L., Len
gyel E. Molecular changes driving low-grade
serous ovarian cancer and implications for
treatment. Int. J. Gynecol. Cancer. 2024. 34(10):
1630–1638.
https://doi.org/10.1136/ijgc-2024-005305.
63. Musacchio L., Lorusso D., Sabetta G. et al. Ad-
vances in treatment strategies for low-grade
serous ovarian cancer. Cancer Treat. Rev. 2025.
5: 103019.
https://doi.org/10.1016/j.ctrv.2025.103019.
64. Manning-Geist B.L., Cantor T., O’Cearbhaill
R.E., Grisham R.N. Redefining the standard of
care for low-grade serous ovarian cancer. Clin.
Adv. Hematol. Oncol. 2024. 22(5): 205–226.
https://doi:10.36053/ho-2205-0001.
65. Mai N., Fernandez N., Drilon A., Chakravar-
ty D. Precision Oncology: 2025 in Review.
Cancer Discov. 2025. 15(12): 2414–2421.
https://doi.org/10.1158/2159-8290.CD-25-1784.
66. Isermann T., Sers C., Der C.J., Papke B. KRAS
inhibitors: resistance drivers and combina-
torial strategies. Trends Cancer. 2025. 11(2):
91–116.
https://doi:10.1016/j.trecan.2024.11.009.
67. Ilkura H., Hyoudoh I., Aoki T. et al. US Patent
US7897792 (2011).
68. Keam S.J. Imlunestrant: First Approval. Drugs.
2026. 86(1): 135–141.
https://doi.org/10.1007/s40265-025-02266-x.
69. Corti C., De Angelis C., Bianchini G. et al.
Novel endocrine therapies: What is next in es-
trogen receptor positive, HER2 negative breast
cancer? Cancer Treat. Rev. 2023. 117: 102569.
https://doi.org/10.1016/j.ctrv.2023.102569.
70. Sahin T.K., Aksoy S., Guven D.C. Oral selec-
tive estrogen receptor degraders (SERDs) in
hormone receptor-positive HER2-negative
metastatic breast cancer after progression with
CDK4/6 inhibitors. Expert Rev. Anticancer
Therapy. 2025. 25(5): 471–484.
https://doi.org/10.1080/14737140.2025.24796
04.
71. Guglielmi G., Del Re M., Gol L.S. et al. Phar-
macological insights on novel oral selective
estrogen receptor degraders in breast cancer.
Eur. J. Pharmacol. 2024. 969: 176424.
https://doi.org/10.1016/j.ejphar.2024.176424.
72. Bastian J.A., Cohen J.D., Rubio A. et al. US
Patent US0234960 (2023).
73. Wzorek A., Klika K.D., Han J. et al. Enantio
mer Purification Through Achiral Chroma-
tography: Integrating Simulated Moving Bed
and Self-Disproportionation of Enantiomers.
Ukr. Chem. J. 2025. 91(3): 34–48.
https://doi.org/10.33609/2708-129X.91.3.
2025.34-48.
74. Marek W.K., Lee J.W., Seidel-Morgenstern A.,
Antos D. Separation of nonracemic mixtures
of enantiomers by achiral simulated moving
bed chromatography. Sep. Purif. Tech. 2025.
361: 131497.
https://doi.org/10.1016/j.seppur.2025.131497.
75. Mruc P., Olbrycht M., Korbetskyy M., Antos
D. Altering the mobile phase composition to
76 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
enhance self-disproportionation of enantio
mers in achiral chromatography. J. Chrom. A.
2024. 1715: 464603.
https://doi.org/10.1016/j.chroma.2023.464
603.
76. Fiskus W., Daver N., Boettcher S. et al. Acti
vity of menin inhibitor ziftomenib (KO-539)
as monotherapy or in combinations against
AML cells with MLL1 rearrangement or mu-
tant NPM1. Leukemia. 2022. 36(11): 2729–33.
https://doi.org/10.1038/s41375-022-01707-w.
77. Fathi A.T., Issa G.C., Wang E.S. et al. Zifto
menib combined with venetoclax/azacitidine
in relapsed/refractory NPM1-m or KMT2A-r
acute myeloid leukemia: interim phase 1a re-
sults from KOMET-007. Blood. 2024. 144:
2880.
https://doi.org/10.1182/blood-2024-199170.
78. Wang E.S., Montesinos P., Foran J. et al. Zift-
omenib in relapsed or refractory NPM1-mu-
tated AML. J. Clin. Oncol. 2025. 43(31): 3381–
3390.
https://doi:10.1200/JCO-25-01694.
79. Zeidan A.M., Wang E.S., Issa G.C. et al. Zifto
menib combined with intensive induction
(7+3) in newly diagnosed NPM1-m or KM-
T2A-r acute myeloid leukemia: interim phase
1a results from KOMET-007. Blood. 2024. 144:
214.
https://doi.org/10.1182/blood-2024-198218.
80. Wu T., Li L., Wang Y., Ren P., Grembecka J.,
Cierpicki T., Klossowski S., Pollock J., Borkin D.
WO 2017/161028 A1 (2017).
81. Wu T., Li L., Ren P. US 11649251 B2 (2023).
82. Heist R.S., Sands J., Bardia A. et al. Clinical
management, monitoring, and prophylaxis of
adverse events of special interest associated
with datopotamab deruxtecan. Cancer Treat.
Rev. 2024. 125: 102720.
https://doi.org/10.1016/j.ctrv.2024.102720.
83. Blair H.A. Datopotamab Deruxtecan: First
Approval. Drugs. 2025. 85(7): 965–975.
https://doi.org/10.1007/s40265-025-02185-x.
84. Okajima D., Yasuda S., Maejima T. et al. Dato-
potamab deruxtecan, a novel TROP2-directed
antibody–drug conjugate, demonstrates po-
tent antitumor activity by efficient drug deli
very to tumor cells. Mol. Cancer Therap. 2021.
20(12): 2329–2340.
https://doi.org/10.1158/1535-7163.MCT-21-0
206.
85. Bardia A., Krop I.E., Kogawa T. et al. Dato-
potamab deruxtecan in advanced or metasta
tic HR+/HER2–and triple-negative breast can-
cer: results from the phase I TROPION-Pan-
Tumor01 study. J. Clin. Oncol. 2024. 42(19):
2281–2294.
https://doi:10.1200/JCO.23.01909.
86. Shimizu T., Sands J., Yoh K. et al. First-in-hu-
man, phase I dose-escalation and dose-expan-
sion study of trophoblast cell-surface antigen
2-directed antibody–drug conjugate dato-
potamab deruxtecan in non-small cell lung
cancer: TROPION-PanTumor01. J. Clin. On-
col. 2023. 41(29): 4678–4687.
https://doi:10.1200/JCO.23.00059.
87. Alla V., Rao R., Ramarao C. et al. PT
WO2012032531A1 (2012).
88. Flick A.C., Leverett C.A., Ding H.X. et al. Syn-
thetic Approaches to the New Drugs Approved
during 2019. J. Med. Chem. 2021. 64(7): 3604–
3657.
https://doi.org/10.1021/acs.jmedchem.1c0
0208.
89. Papadopoulos K.P., Borazanci E., Shaw A.T.
et al. US phase I first-in-human study of tale-
trectinib (DS-6051b/AB-106), a ROS1/TRK
inhibitor, in patients with advanced solid tum-
ors. Clin. Cancer Res. 2020. 26(18): 4785–4794.
https://doi.org/10.1158/1078-0432.CCR-20-
1630.
90. Zhang T., Zou Y., Zhang S.H. et al. Taletrecti
nib promotes pyroptosis in colorectal carcino-
ma via SRC/AKT/mTOR axis inhibition. Sci.
Rep. 2025. 15(1): 18049.
https://doi.org/10.1038/s41598-025-02901-3.
91. Pérol M., Li W., Pennell N.A. et al. Taletrectinib
in ROS1+ non-small cell lung cancer: TRUST.
J. Clin. Oncol. 2025. 43(16): 1920–1929.
https://doi:10.1200/JCO-25-00275.
92. Khan I., Sahar A., Numra S. et al. Efficacy and
safety of taletrectinib for treatment of ROS1
positive non-small cell lung cancer: A system-
atic review. Expert Opin. Pharmacother. 2025.
26(6): 765–772.
https://doi.org/10.1080/14656566.2025.24871
50.
93. Nagasaka M., Brazel D., Ou S.H. Taletrectinib
77https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Karel D. Klika, Nataliya V. Lyutenko, Vadim A. Soloshonok UCJ № 4/ Vol. 92
for the treatment of ROS-1 positive non-small
cell lung cancer: a drug evaluation of phase I
and II data. Expert Opin. Investig. Drugs. 2024.
33(2): 79–84.
https://doi.org/10.1080/13543784.2024.23051
31.
94. Zhou F., Chen D.D., Li P., Lu J., Xue J. PT
WO2023272701 (2023).
95. Takeda Y., Yoshikawa K., Kagoshima Y. PT
WO2013183578A1 (2013).
96. De Camp W.H. Chiral drugs: The FDA per-
spective on manufacturing and control. J.
Pharm. Biomed. Anal. 1993. 11(11–12): 1167–
1172.
https://doi.org/10.1016/0731-7085(93)80100-F.
97. Daniels J.M., Nestmann E.R., Kerr A. Develop-
ment of stereoisomers (chiral) drugs: A brief
review of scientific and regulatory considera-
tions. Drug Inf. J. 1997. 31(3): 639–646.
https://doi.org/10.1177/009286159703100303.
98. De Camp W.H. The FDA perspective on the
development of stereoisomers. Chirality. 1989.
1(1): 2–6.
https://doi.org/10.1002/chir.530010103.
99. Nakamura T., Tateishi K., Tsukagoshi S. et
al. Self-Disproportionation of Enantiomers
of Non-racemic Chiral Amine Derivatives
Through Achiral Chromatography. Tetrahe-
dron. 2012. 68: 4013–4017.
https://doi:10.1016/j.tet.2012.03.054.
100. Soloshonok V.A. Remarkable amplification of
the self‐disproportionation of enantiomers on
achiral‐phase chromatography columns. An-
gew. Chem., Int. Ed. 2006. 45(5): 766–769.
https://doi.org/10.1002/anie.200503373.
101. Soloshonok V.A., Ueki H., Yasumoto M. et al.
Phenomenon of optical self-purification of
chiral non-racemic compounds. J. Am. Chem.
Soc. 2007. 129(40): 12112–12113.
https://doi:10.1021/ja065603a.
102. Soloshonok V.A., Klika K.D. Terminology re-
lated to the phenomenon ‘self-disproportiona-
tion of enantiomers’ (SDE). Helv. Chim. Acta.
2014. 97(11): 1583–1589.
https://doi:10.1002/hlca.201400122.
103. Ueki H., Yasumoto M., Soloshonok V.A. Ra-
tional application of self-disproportionation
of enantiomers via sublimation—a novel
methodological dimension for enantiomeric
purifications. Tetrahedron: Asymmetry. 2010.
21(11–12): 1396–1400.
https://doi:10.1016/j.tetasy.2010.04.040.
104. Sorochinsky A.E., Katagiri T., Ono T. et al.
Optical purifications via self-disproportiona-
tion of enantiomers by achiral chromatogra-
phy; Case study of a series of α-CF3-contain-
ing secondary alcohols. Chirality. 2013. 25(6):
365–368.
https://doi:10.1002/chir.22180.
105. Sorochinsky A.E., Aceña J.L., Soloshonok V.A.
Self-disproportionation of enantiomers of chi-
ral, non-racemic fluoroorganic compounds:
Role of fluorine as enabling element. Synthesis.
2013. 45(2): 141–152.
https://doi:10.1055/s-0032-1316812.
106. Han J., Wzorek A., Kwiatkowska M. et al. The
self-disproportionation of enantiomers (SDE)
of amino acids and their derivatives. Amino
Acids. 2019. 51(6): 865–889.
https://doi:10.1007/s00726-019-02729-y.
107. Wzorek A., Sato A., Drabowicz J. et al. Remar
kable magnitude of the self-disproportiona-
tion of enantiomers (SDE) via achiral chro-
matography; application to the practical-scale
enantiopurification of b-amino acid esters.
Amino Acids. 2016. 48(2): 605–613.
https://doi:10.1007/s00726-015-2152-5.
108. Hosaka T., Imai T., Wzorek A. et al. The
self-disproportionation of enantiomers (SDE)
of a-amino acid derivatives; facets of steric
and electronic properties. Amino Acids. 2019.
51(2): 283–294.
https://doi.org/10.1007/s00726-018-2664-x.
109. Soloshonok V.A., Wzorek A., Klika K.D.
A question of policy: should tests for the self-
disproportionation of enantiomers (SDE) be
mandatory for reports involving scalemates?
Tetrahedron: Asymmetry. 2017. 28(10): 1430–
1434.
https://doi:10.1016/j.tetasy.2017.08.020.
110. Han J., Soloshonok V.A., Klika K.D. et al. Chi-
ral sulfoxides: advances in asymmetric synthe-
sis and problems with the accurate determi-
nation of the stereochemical outcome. Chem.
Soc. Rev. 2018. 47(4): 1307–1350.
https://doi:10.1039/c6cs00703a.
111. Soloshonok V.A., Roussel C., Kitagawa O.,
Sorochinsky A.E. Self-disproportionation of
78 ISSN 2708-129X. Укр. хім. журн., 2026
ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED
ANTICANCER DRUGS IN 2025 (review).ORGANIC CHEMISTRY
enantiomers via achiral chromatography: a
warning and extra dimension in optical puri-
fications. Chem. Soc. Rev. 2012. 41(11): 4180–
4188.
https://doi:10.1039/C2CS35006H.
112. Han J., Kitagawa O., Wzorek A. et al. The
self-disproportionation of enantiomers (SDE):
a menace or an opportunity? Chem. Sci. 2018.
9(7): 1718–1739.
https://doi:10.1039/C7SC05138G.
113. Han J., Dembinski R., Soloshonok V.A., Klika
K.D. A call for a change in policy regarding the
necessity for SDE tests to validate the veracity
of the outcome of enantioselective syntheses,
the inherent chiral state of natural products,
and other cases involving enantioenriched
samples. Molecules. 2021. 26(13): 3994.
https://doi.org/10.3390/molecules26133994.
114. Han J., Wzorek A., Klika K.D., Soloshonok
V.A. Recommended tests for the self-dispro-
portionation of enantiomers (SDE) to ensure
accurate reporting of the stereochemical out-
come of enantioselective reactions. Molecules.
2021. 26(9): 2757.
https://doi.org/10.3390/molecules26092757.
115. Yasumoto M., Ueki H., Ono T. et al. Self-Dis-
proportionation of Enantiomers via Sublima-
tion: Isopropyl 3,3,3-(Trifluoro)-Lactate. J.
Fluor. Chem. 2010. 131: 535–539.
https://doi.org/10.1016/j.jfluchem.2009.11.026.
116. Yasumoto M., Ueki H., Soloshonok V.A.
Self-disproportionation of enantiomers of
3,3,3-trifluorolactic acid amides via sublima-
tion. J. Fluor. Chem. 2010. 131(2): 266–269.
https://doi.org/10.1016/j.jfluchem.2009.10. 002.
117. Albrecht M., Soloshonok V.A., Schrader L. et
al. Chirality-dependent sublimation of α-(tri-
fluoromethyl)-lactic acid: Relative vapor pres-
sures of racemic, eutectic, and enantiomerical-
ly pure forms, and vibrational spectroscopy of
isolated (S,S) and (S,R) dimers. J. Fluor. Chem.
2010. 131(4): 495–504.
https://doi.org/10.1016/j.jfluchem.2009.11.015.
118. Yasumoto M., Ueki H., Soloshonok V.A. Self-
disproportionation of enantiomers of α-trif-
luoromethyl lactic acid amides via sublima-
tion. J. Fluor. Chem. 2010. 131(4): 540–544.
https://doi.org/10.1016/j.jfluchem.2009.11.010.
119. Han J., Kiss L., Mei H. et al. Chemical aspects
of human and environmental overload with
fluorine. Chem. Rev. 2021. 121(8): 4678–4742.
doi.org/10.1021/acs.chemrev.0c01263.
120. Kanduti D., Sterbenk P., Artnik B. Fluoride: a
review of use and effects on health. Mater. So-
ciomMed. 2016. 28(2): 133.
https://doi:10.5455/msm.2016.28.133-137.
121. Zuo H., Chen L., Kong M. et al. Toxic effects
of fluoride on organisms. Life Sci. 2018. 198:
18–24.
https://doi.org/10.1016/j.lfs.2018.02.001.
122. Ghosh A., Mukherjee K., Ghosh S.K., Saha B.
Sources and toxicity of fluoride in the environ-
ment. Res. Chem. Intermed. 2013. 39: 2881–
2915.
https://doi.org/10.1007/s11164-012-0841-1.
123. Holaday D.A., Fiserova-Bergerova V. Fate of
fluorinated metabolites of inhalation anes-
thetics in man. Drug Metab. Rev. 1979. 9(1):
61–78.
https://doi.org/10.3109/03602537909046434.
124. Jeschke P. Current trends in the design of fluo
rine‐containing agrochemicals. Ch. 11. In:
Organofluorine chemistry: Synthesis, modeling,
and applications. Szabó K., Selander N. (Eds.).
2021. 363–395.
https://doi.org/10.1002/9783527825158.ch11.
125. Brunn H., Arnold G., Körner W. et al. PFAS:
forever chemicals—persistent, bioaccumu-
lative and mobile. Reviewing the status and
the need for their phase out and remediation
of contaminated sites. Environ. Sci. Eur. 2023.
35(1): 1–50.
https://doi.org/10.1186/s12302-023-00721-8.
126. Han J., Wzorek A., Klika K.D. et al. Bioavaila-
ble Plastic: From Cognitive Decline in the Old
to Hormonal Disruption in the Young. Ukr.
Chem. J. 2025. 91(5): 33–62.
https://doi:10.33609/2708-129X.91.5.2025.33-62.
Стаття надійшла: 28.03.2026.
Статтю прийнято до друку: 09.05.2026.
Статтю опубліковано: 25.05.2026.
|
| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-777 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:14:36Z |
| publishDate | 2026 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/34/e637f380282e5e436b2b815bd8d4b634.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7772026-07-22T08:23:57Z ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review) Wzorek, Alicja Ono, Taizo Klika, Karel Lyutenko , Natalia Soloshonok, Vadim Fluorine; Drug Design; Oncology; Synthesis; Chirality; Pharmacology; Therapeutics. In 2025, seven fluorine-containing anticancer agents received approval from the US Food and Drug Administration, underscoring the continued and growing impact of strategic fluorination in modern oncology drug design. These newly authorized therapies represent a diverse portfolio spanning a broad spectrum of malignancies, molecular targets, and innovative mechanisms of action, further validating fluorine’s unique ability to enhance drug performance. Sunvozertinib (Zegfrovy®) was approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring specific EGFR mutations. The combination of defactinib and avutometinib (Avmapki®) provides a much-needed targeted option for patients with KRAS-mutated recurrent low-grade serous ovarian cancer, addressing a historically challenging disease setting. Imlunestrant (Inluriyo®) offers a next-generation selective estrogen receptor degrader (SERD) as an effective endocrine therapy for estrogen receptor-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Ziftomenib (Komzifti®) enables precision therapy for adults with relapsed or refractory (AML) carrying susceptible NPM1 mutations, representing a significant advancement in targeted hematologic oncology.Datopotamab deruxtecan (Datroway®), a novel TROP2-directed antibody–drug conjugate (ADC) with a topoisomerase I inhibitor payload, expands treatment options for previously treated hormone receptor-positive, HER2-negative metastatic breast cancer and for certain TKI-experienced NSCLC populations. Taletrectinib (Ibtrozi®), a potent next-generation ROS1 tyrosine kinase inhibitor, received approval for ROS1-positive NSCLC in both TKI-naïve and TKI-experienced patients, offering improved central nervous system penetration and activity against resistant mutations.Collectively, these seven agents vividly illustrate the remarkable versatility of fluorine incorporation in enhancing molecular potency, metabolic stability, binding selectivity, and overall pharmacokinetic performance across vastly different therapeutic modalities — from small-molecule kinase inhibitors and degraders to complex antibody–drug conjugates. The strategic placement of fluorine atoms or fluorinated groups in these molecules often leads to improved lipophilicity, stronger target engagement, reduced clearance, and better safety profiles.For each compound, we provide a comprehensive integrated discussion covering its discovery history, detailed biological mechanism of action, primary therapeutic applications, recommended clinical administration and dosing regimens, the specific role of fluorination in optimizing its pharmacological and physicochemical properties, as well as the detailed chemical synthesis routes employed in its industrial-scale production. V.I.Vernadsky Institute of General and Inorganic Chemistry 2026-05-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/777 10.33609/2708-129X.92.4.2026.52-78 Ukrainian Chemistry Journal; Vol. 92 No. 4 (2026): Ukrainian Chemistry Journal; 52-78 Украинский химический журнал; ##issue.vol## 92 ##issue.no## 4 (2026): Ukrainian Chemistry Journal; 52-78 Український хімічний журнал; Том 92 № 4 (2026): Ukrainian Chemistry Journal; 52-78 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/777/410 Copyright (c) 2026 Alicja Wzorek, Taizo Ono, Karel Klika, Natalia Lyutenko , Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Wzorek, Alicja Ono, Taizo Klika, Karel Lyutenko , Natalia Soloshonok, Vadim ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review) |
| title | ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review) |
| title_full | ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review) |
| title_fullStr | ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review) |
| title_full_unstemmed | ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review) |
| title_short | ORGANOFLUORINE CHEMISTRY IN ONCOLOGY: A REVIEW OF US FDA-APPROVED ANTICANCER DRUGS IN 2025 (review) |
| title_sort | organofluorine chemistry in oncology: a review of us fda-approved anticancer drugs in 2025 (review) |
| topic_facet | Fluorine Drug Design Oncology Synthesis Chirality Pharmacology Therapeutics. |
| url | https://ucj.org.ua/index.php/journal/article/view/777 |
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