Nguyen Minh H, Wang Anlai, Truong Lisa, Zhang Ke, Ye Hai-Fen, Zhao Peng, Horsey April, Frascella Michelle, Leffet Lynn, Federowicz Kelly, Behshad Elham, Witten Michael R, Qi Chao, Xu Yao, Jalluri Ravi, Harris Jennifer J, Hess Rodrigo, Sayers Brian, Lin Luping, Yeleswaram Swamy, Zhang Guofeng, Kim Sunkyu, Covington Maryanne, Diamond Sharon, Yao Wenqing, Vechorkin Oleg
Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
ACS Med Chem Lett. 2025 May 17;16(6):1182-1189. doi: 10.1021/acsmedchemlett.5c00232. eCollection 2025 Jun 12.
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.
成纤维细胞生长因子受体（FGFRs）是公认的肿瘤学靶点，FGFR2和FGFR3的异常激活与多种肿瘤类型有关，包括胆管癌和尿路上皮癌。目前获批的FGFR2/3靶向疗法依赖于泛FGFR小分子激酶抑制剂，这些抑制剂常常由于意外抑制FGFR1和FGFR4以及由守门基因突变导致的获得性耐药而引发脱靶毒性。在此，我们报告了INCB126503的发现，这是一种高效、口服生物利用度良好的FGFR2/3抑制剂，具有出色的异构体选择性以及对守门人突变体的等效活性。INCB126503在体内有效抑制FGFR信号传导而不诱导高磷血症，并且在携带FGFR3基因改变的异种移植模型中显示出显著的抗肿瘤疗效。
