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

  • ACS Med Chem Lett. 2023 Mar 10;14(4):396-404. doi: 10.1021/acsmedchemlett.3c00006.
Satoru Ito  1 ,  Sachie Otsuki  1 ,  Hirokazu Ohsawa  1 ,  Atsushi Hirano  1 ,  Hideki Kazuno  2 ,  Satoshi Yamashita  1 ,  Kosuke Egami  3 ,  Yoshihiro Shibata  4 ,  Ikuo Yamamiya  1 ,  Fumiaki Yamashita  1 ,  Yasuo Kodama  1 ,  Kaoru Funabashi  1 ,  Hiromi Kazuno  1 ,  Toshiharu Komori  5 ,  Satoshi Suzuki  1 ,  Hiroshi Sootome  1 ,  Hiroshi Hirai  1 ,  Takeshi Sagara  1
Affiliations
  • 1. Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
  • 2. Formulation Research Lab, CMC Division, Taiho Pharmaceutical Co. Ltd., Tokushima, Tokushima 771-0194, Japan.
  • 3. Intellectual Property Department, Taiho Pharmaceutical Co. Ltd., 1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo 101-8444, Japan.
  • 4. MA Project Management Office, Taiho Pharmaceutical Co. Ltd., 1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo 101-8444, Japan.
  • 5. Regulatory Affairs Department, Taiho Pharmaceutical Co. Ltd., 1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo 101-8444, Japan.
PMID: 37077386 DOI: 10.1021/acsmedchemlett.3c00006
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.