Discovery of INCB126503 as a Potent and Selective FGFR2/3 Inhibitor

  • ACS Med Chem Lett. 2025 May 17;16(6):1182-1189. doi: 10.1021/acsmedchemlett.5c00232.
Minh H Nguyen  1 ,  Anlai Wang  1 ,  Lisa Truong  1 ,  Ke Zhang  1 ,  Hai-Fen Ye  1 ,  Peng Zhao  1 ,  April Horsey  1 ,  Michelle Frascella  1 ,  Lynn Leffet  1 ,  Kelly Federowicz  1 ,  Elham Behshad  1 ,  Michael R Witten  1 ,  Chao Qi  1 ,  Yao Xu  1 ,  Ravi Jalluri  1 ,  Jennifer J Harris  1 ,  Rodrigo Hess  1 ,  Brian Sayers  1 ,  Luping Lin  1 ,  Swamy Yeleswaram  1 ,  Guofeng Zhang  1 ,  Sunkyu Kim  1 ,  Maryanne Covington  1 ,  Sharon Diamond  1 ,  Wenqing Yao  1 ,  Oleg Vechorkin  1
Affiliations
  • 1. Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
PMID: 40529099 DOI: 10.1021/acsmedchemlett.5c00232
Abstract

Fibroblast Growth Factor receptors (FGFRs) are well-established oncology targets, with aberrant FGFR2 and FGFR3 activation implicated in multiple tumor types, including cholangiocarcinoma and urothelial carcinoma. Currently approved FGFR2/3-targeted therapies rely on pan-FGFR small-molecule kinase inhibitors, which often lead to off-target toxicities due to unintended inhibition of FGFR1 and FGFR4, as well as acquired resistance driven by gatekeeper mutations. Herein, we report the discovery of INCB126503, a highly potent, orally bioavailable FGFR2/3 inhibitor with excellent isoform selectivity and equipotent activity against gatekeeper mutants. INCB126503 effectively suppresses FGFR signaling in vivo without inducing hyperphosphatemia and demonstrates significant antitumor efficacy in xenograft models harboring FGFR3 genetic alterations.

Keywords
FGFR; isoform selectivity; structure-based drug design; structure−activity relationship; xenograft models.
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