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

Satoru Ito, Sachie Otsuki, Hirokazu Ohsawa, Atsushi Hirano, Hideki Kazuno, Satoshi Yamashita, Kosuke Egami, Yoshihiro Shibata, Ikuo Yamamiya, Fumiaki Yamashita, Yasuo Kodama, Kaoru Funabashi, Hiromi Kazuno, Toshiharu Komori, Satoshi Suzuki, Hiroshi Sootome, Hiroshi Hirai, and Takeshi Sagara

ACS Medicinal Chemistry Letters 2023 14 (4), 396-404

DOI: 10.1021/acsmedchemlett.3c00006

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.