Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use

Abstract

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1−4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I−III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

Synthetic Approaches to the New Drugs Approved During 2022

“…230,231 The oral, smallmolecule cancer treatment was granted accelerated approval in the US by the USFDA in late September 2022 and serves as an irreversible inhibitor and selective covalent binder of fibroblast growth factor receptor (FGFR) 1−4. 232,233 As deregulated FGFR signaling (which can result from chromosomal rearrangement, mutation, upregulation, and amplification of FGFR) can alter tissue homeostasis and can ultimately lead to carcinogenesis, inhibition of this receptor serves as a promising therapeutic approach for cancer treatments. 234,235 The discovery route for the synthesis of futibatinib (32) was disclosed by Taiho Pharmaceutical and is displayed in Scheme 56.…”

“…Futibatinib ( 32 ) is under development by Taiho Pharmaceutical and Taiho Oncology for treatment of numerous cancer types: breast cancer, cholangiocarcinoma, gastric cancer, nonsmall cell lung cancer, esophageal cancer, and urothelial cancer. , The oral, small-molecule cancer treatment was granted accelerated approval in the US by the USFDA in late September 2022 and serves as an irreversible inhibitor and selective covalent binder of fibroblast growth factor receptor (FGFR) 1–4. , As deregulated FGFR signaling (which can result from chromosomal rearrangement, mutation, upregulation, and amplification of FGFR) can alter tissue homeostasis and can ultimately lead to carcinogenesis, inhibition of this receptor serves as a promising therapeutic approach for cancer treatments. , …”

“…The discovery route for the synthesis of futibatinib ( 32 ) was disclosed by Taiho Pharmaceutical and is displayed in Scheme . Activation of alcohol 32.1 with base and methanesulfonyl chloride enabled facile nucleophilic substitution with amine 32.2 .…”

Structure–Activity Relationship Study and Design Strategies of Hydantoin, Thiazolidinedione, and Rhodanine-Based Kinase Inhibitors: A Two-Decade Review

“…16 Futibatinib was the first FGFR covalent inhibitor that gained FDA approval in 2022. 17 Five SMKIs (ibrutinib, osimertinib, palbociclib, upadacitinib, abemaciclib) are included in the top 50 drug sales in the 2022 survey, with ibrutinib sales reaching around US$ 8.35 billion. 18 Despite these advancements, the field of kinase inhibitors have faced persistent challenges due to drug resistance, necessitating ongoing research and development efforts.…”

“…Asciminib (2021) is an allosteric inhibitor that binds into the BCR-ABL kinase’s myristoyl pocket . Futibatinib was the first FGFR covalent inhibitor that gained FDA approval in 2022 . Five SMKIs (ibrutinib, osimertinib, palbociclib, upadacitinib, abemaciclib) are included in the top 50 drug sales in the 2022 survey, with ibrutinib sales reaching around US$ 8.35 billion …”