Design, Synthesis, and Biological Evaluation of 5‑Formyl-pyrrolo[3,2‑b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 65; no. 21; pp. 14809 - 14831
• Main Authors: Yang, Fang, Chen, Xiaojuan, Song, Xiaojuan, Ortega, Raquel, Lin, Xiaojing, Deng, Wuqing, Guo, Jing, Tu, Zhengchao, Patterson, Adam V., Smaill, Jeff B., Chen, Yongheng, Lu, Xiaoyun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.11.2022; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; IDENTIFICATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01319

The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo­[3,2-b]­pyridine derivatives as new reversible-covalent inhibitors targeting wild-type and gatekeeper mutant variants of FGFR4 kinase. The representative compound 10z exhibited single-digit nanomolar activity against wild-type FGFR4 and the FGFR4V550L/M mutant variants in biochemical and Ba/F3 cellular assays, while sparing FGFR1/2/3. Furthermore, 10z showed significant antiproliferative activity against Hep3B, JHH-7, and HuH-7 HCC cells with IC50 values of 37, 32, and 94 nM, respectively. MALDI-TOF-MS and X-ray protein crystallography studies were consistent with 10z acting as a reversible-covalent inhibitor of FGFR4, serving as a promising lead compound for further anticancer drug development.