INCB126503作为一种有效的选择性FGFR2/3抑制剂的发现

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-05-17 eCollection Date: 2025-06-12 DOI:10.1021/acsmedchemlett.5c00232

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

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引用次数: 0

摘要

成纤维细胞生长因子受体（FGFRs）是公认的肿瘤靶点，其异常的FGFR2和FGFR3激活与多种肿瘤类型有关，包括胆管癌和尿路上皮癌。目前批准的fgfr2 /3靶向治疗依赖于泛fgfr小分子激酶抑制剂，由于FGFR1和FGFR4的意外抑制以及由看门人突变驱动的获得性耐药，这些抑制剂经常导致脱靶毒性。在此，我们报告了INCB126503的发现，这是一种高效的口服生物可利用的FGFR2/3抑制剂，具有出色的异构体选择性和对看门人突变的等效活性。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功效。

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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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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.