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Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Mar 10; Vol. 14 (4), pp. 396-404. Date of Electronic Publication: 2023 Mar 10 (Print Publication: 2023). - Publication Year :
- 2023
-
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.<br />Competing Interests: The authors declare the following competing financial interest(s): All authors are employees of Taiho Pharmaceutical Co. Ltd.<br /> (© 2023 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 14
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 37077386
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.3c00006