2. Academic Validation
  3. Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use

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

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.

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