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Compound 1 was selected for further characterization and named as futibatinib.
The high selectivity of futibatinib (1) for FGFR1–4 was confirmed by testing the activesite directed competition binding assay using a KINOMEscan panel containing 387 wildtype kinases. Among the 387 kinases other than FGFR1–4, only two kinases exhibited
>50% inhibition by futibatinib (1) at 100 nM: Mitogen-activated protein kinase 12
(MAPK12; 69%) and insulin receptor (INSR; 55%). Then the enzyme-inhibitory
activities of MAPK12 and INSR were tested in cell-free enzyme assays, and the
inhibition of these two kinases by futibatinib (1) was limited. Thus, these results suggest
that futibatinib (1) is a highly potent and selective covalent FGFR1−4 inhibitor.
Chemistry and Pharmacology of Drug Discovery
4 Pharmacokinetics and Drug Metabolism
The pharmacokinetic properties of oral futibatinib (1) 20 mg qd (once daily) have been
evaluated in patients with advanced solid tumors. Futibatinib (1) exposure increased in a
dose-proportional manner over a dose range of 4–24 mg.
of futibatinib (1), the maximum plasma concentration is achieved at 2 h while the
geometric mean apparent volume of distribution of futibatinib (1) is 66 L. Futibatinib (1)
is 95% bound to human plasma protein. It bound primarily
glycoprotein.
CYP2C9 and CYP2D6 as well as by glutathione conjugation. The mean elimination halflife of futibatinib (1) is 2.9 h with mean apparent clearance of 20 L/h. After a single
20 mg oral dose of radiolabeled futibatinib (1) administration, nearly 91% of the total
radioactivity was recovered in feces and 9% in urine. The pharmacokinetics of futibatinib
(1) are not significantly affected by age, sex, race, or body weight.
futibatinib (1) may increase its exposure which may as a result increase the incidence and
severity of adverse reactions. Similarly, the concomitant use of drugs that are dual P-gp
and strong CYP3A inducers may decrease futibatinib (1) exposure, which may reduce the
efficacy of futibatinib (1).
15
Futibatinib (1) is mainly metabolized by CYP3A, and to a lesser extent by
Concomitant use of drugs that are dual P-gp and strong CYP3A inhibitors with
15
On 20 mg oral administration
to albumin and α1-acid
5 Efficacy and Safety
Efficacy of futibatinib (1) was evaluated in TAS-120-101 (NCT02052778), a multicenter,
open-label, single-arm trial that enrolled 103 patients with previously treated,
unresectable, locally advanced/metastatic intrahepatic cholangiocarcinoma harboring a
FGFR2 gene fusion or other rearrangement. Patients received 20 mg of futibatinib (1)
orally once daily until disease progression or unacceptable toxicity.
outcome measures were overall response rate (ORR) and duration of response (DoR) as
determined by an independent review committee according to RECIST v1.1. ORR was
The major efficacy
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Chapter 7. Futibatinib (Lytgobi)
42% (95% Confidence Interval [CI]: 32, 52) in 103 evaluable patients. In the overall
population, the median DoR was 9.7 months (95% CI 7.6–17.1); DoR was ≥6 and ≥12
months in 72% and 14% of responders, respectively. Disease control rate was 82.5%,
median progression-free survival (PFS) was 9.0 months and median overall survival (OS)
15
was 21.7 months (12-month OS rate 72%).
Besides the use of futibatinib (1) in intrahepatic cholangiocarcinoma, a phase II
clinical trial (NCT04189445) is evaluating futibatinib (1) in tumors with specific FGFR
aberrations. The phase II clinical trials in patients with urothelial cancer (NCT04601857)
and breast cancer (NCT04024436; FOENIX-MBC2) are ongoing too. A phase Ib/II trial
(NCT04965818) is evaluating futibatinib (1) in combination with binimetinib (a MEK
inhibitor) in patients with KRAS mutation-positive advanced NSCLC. The phase Ib trial
(JapicCTI-195063) of futibatinib (1) in combination with pembrolizumab in patients
having advanced solid tumors, including esophageal cancer, is also ongoing.
The most common adverse reactions of futibatinib (1) occurring in 20% or more
of patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry
mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye,
nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia
syndrome, and vomiting. The most common serious side effects of futibatinib (1) (which
may affect more than 1% of patients), include intestinal obstruction and migraine.
6 Synthesis
Th first synthesis of futibatinib (1) was disclosed in a patent by Taiho pharmaceutical in
16
Recently, synthesis of futibatinib (1) was published as the supplemental
2013.
information (SI) of Taiho’s 2023 ACS Medicinal Chemistry Letter article.
13
Starting from
pyrazolopyrimidine 21, nucleophilic substitution reaction was applied to install the chiral
moiety pyrrolidine 22 to give 23 with chiral center inversion (48% yield). In the next
step, by Sonogashira coupling reaction, the arylalkyne 24 was coupled with 23 to afford
25 with excellent 96% yield. Compound 25 was then treated with 4 N HCl solution in
1,4-dioxane for the deprotection of Boc to get 26. Compound 26 was used in the next step
without further purification and was treated with acryloyl chloride in the presence of
TEA and chloroform to get the target compound 1 with good yield 84% in the two steps.
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Chemistry and Pharmacology of Drug Discovery
The same company reported the synthesis of futibatinib (1) in 2015. In this
synthetic route, the sequence of Sonogashira coupling and SN2 reaction was reversed to
get 25 and then followed by deprotection and acylation to get futibatinib (1).
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The original medicinal chemistry synthesis of futibatinib (1) as described above
proved sufficient for the delivery of multigram quantities; however, several issues with
this approach necessitated further optimization of the synthetic route to facilitate future
scale-up activities. First, the original synthetic route had silica gel column
chromatography purification, while chloroform was used as the reaction solvent, although
it is not preferable for commercial production of API. Second, it is important to control
the formation and residual of the main impurity like diamide 28. Several other impurities
are also identified that are not mentioned here. For detail structures of these impurities,
please see Reference 18.
Chapter 7. Futibatinib (Lytgobi)
Considering the above-mentioned problems of the early discovery synthesis, an
alternative approach was needed to synthesize futibatinib (1) on the large-scale
manufacture. Initially the reaction condition using acryloyl chloride was examined,
however, it was difficult to control the formation of compound 28 and a high reaction
conversion rate of futibatinib (1). These problems were resolved by changing the
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acylating reagent from acryloyl chloride to 3-chloropropionyl chloride, the base was
changed to an aqueous sodium hydroxide solution, and the reaction solvent was changed
to a mixture of acetonitrile and water turning out to be biphasic due to the salting-out
effect. So, in the final manufacturing process, the installation of acrylamide covalent
warhead in futibatinib (1) includes a twostep reaction. In the first step compound 26 was
treated with 3-chloropropionyl chloride (29) to obtain 30. In the second step
(elimination), compound 30 is treated with NaOH, after completion of reaction, the
reaction mixture is neutralized by aq. HCl and then crystalized by water to afford crude
futibatinib (1). These two steps, acylation and elimination are biphasic organic−aqueous
system reactions of acetonitrile and water. In the final step of purification, the crude
futibatinib (1) is treated with activated carbon and filtered. Then recrystallization and
drying yielded pure futibatinib (1).
Chemistry and Pharmacology of Drug Discovery
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Chapter 7. Futibatinib (Lytgobi)
7 Summary
Although there are several FGFR inhibitors in the clinical market and several are
currently in clinical development, futibatinib (1) has a unique mechanism of action as an
irreversible covalent FGFR1–4 inhibitor with potential activity against acquired
secondary FGFR kinase domain mutations. In early clinical studies, futibatinib (1)
demonstrated excellent activity in diverse tumor types harboring various FGFR
aberrations. Based on durable and encouraging responses and manageable safety in the
phase II FOENIX-CCA2 study futibatinib (1) was approved for the treatment of patients
with intrahepatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements in
September 2022. The excellent clinical results along with the unique irreversible
mechanism of action, makes futibatinib (1) distinguish from other drugs approved for this
target and sets it apart as a leading second-generation FGFR inhibitor. However, further
studies are required to evaluate mechanisms of acquired resistance to futibatinib (1) and
future opportunities of combination therapies with a view to provide hopes for more
successful treatment in the near future for the patients with intrahepatic
cholangiocarcinoma.
References
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Rees, D. C. Discovery and pharmacological characterization of JNJ42756493 (Erdafitinib), a functionally selective small-molecule FGFR
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7. Kang, C. Infigratinib: first approval. Drugs 2021, 81 (11), 1355–1360.
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Chapter 7. Futibatinib (Lytgobi)
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8
Pacritinib (Vonjo): A Dual JAK2/IRAK1
Inhibitor for Treating Myelofibrosis
Faridoonand
Guiping
1 Background
Pacritinib (Vonjo 1), formerly known as SB1518, is an orally administered, small
molecule JAK2/interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitor that does
not inhibit JAK1. It was developed by CTI BioPharma/S*BIO Pte. Ltd. for the treatment
of conditions such as myelofibrosis and graft-vs-host disease.
normal production of blood cells. It causes extensive scarring in bone marrow, leading to
severe anemia that can cause weakness and fatigue. Bone marrow scarring can also cause
a low number of blood-clotting cells called platelets, which increases the risk of bleeding.
Myelofibrosis often results in an enlarged spleen. Graft-vs-host disease is an immunemediated condition resulting from a complex interaction between donor and recipient
adaptive immunity. It occurs when T cells of donor respond to host histoincompatible
Zhang
Myelofibrosis is a rare type of bone marrow cancer that disrupts the body’s
Chemistry and Pharmacology of Drug Discovery, First Edition. Edited by Jie Jack Li.
© 2025 John Wiley & Sons, Inc. Published 2025 by John Wiley & Sons, Inc.
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