Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.
Satoru ItoSachie OtsukiHirokazu OhsawaAtsushi HiranoHideki KazunoSatoshi YamashitaKosuke EgamiYoshihiro ShibataIkuo YamamiyaFumiaki YamashitaYasuo KodamaKaoru FunabashiHiromi KazunoToshiharu KomoriSatoshi SuzukiHiroshi SootomeHiroshi HiraiTakeshi SagaraPublished in: ACS medicinal chemistry letters (2023)
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.
Keyphrases
- epidermal growth factor receptor
- locally advanced
- cancer therapy
- squamous cell carcinoma
- drug administration
- copy number
- small molecule
- tyrosine kinase
- rectal cancer
- small cell lung cancer
- climate change
- neoadjuvant chemotherapy
- radiation therapy
- advanced non small cell lung cancer
- newly diagnosed
- risk assessment
- genome wide
- combination therapy