Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-<i>b</i>]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors
Fang Yang, Xiaojuan Chen, Xiaojuan Song, Raquel Ortega, Xiaojing Lin, Wuqing Deng, Jing Guo, Zhengchao Tu, Adam V. Patterson, Jeff B. Smaill, Yongheng Chen, Xiaoyun Lu
Abstract
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.