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

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.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-05-17
DOI
https://doi.org/10.1021/acsmedchemlett.5c00232
Citations
4
Primary Topic
Fibroblast Growth Factor Research
Type
article
Field-Weighted Citation Impact
3.22

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article

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

Sunkyu Kim, Ravi Jalluri, Michelle Frascella, Lynn Leffet et al.
4 citations
ACS Medicinal Chemistry Letters
Fibroblast Growth Factor Research
3.22
article

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

Sunkyu Kim, Ravi Jalluri, Michelle Frascella, Lynn Leffet, Anlai Wang, Michael R. Witten, Wenqing Yao, Yao Xu, Peng Zhao, Oleg Vechorkin, Elham Behshad, Hai‐Fen Ye, Swamy Yeleswaram, Chao Qi, Minh H. Nguyen, Brian C. Sayers, Lisa Truong, Jennifer J. Harris, Kelly Federowicz, April Horsey, Ke Zhang, Luping Lin, Guofeng Zhang, Rodrigo Hess, Maryanne Covington, Sharon Diamond
article en
4 citations

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.

ACS Medicinal Chemistry LettersVol. 16(6)
Incyte (United States) (US)
Incyte
Openalex Percentile: Top 8%
Fibroblast Growth Factor Research
3.22
DOISourceOpenAlex
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