4.7 Article

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

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 21, 页码 14809-14831

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01319

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资金

  1. National Key Research and Development Program of China [2018YFE0105800]
  2. National Natural Science Foundation of China [81874285, 81922062]
  3. Guangdong Province Science and Technology Program [2020A0505140007]
  4. Health Research Council of New Zealand [18/1016]
  5. China Maurice Wilkins Centre Collaborative Research Program
  6. Cancer Society Auckland Northland (CSAN)
  7. Jinan University

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In this study, a novel series of reversible-covalent inhibitors targeting wild-type and gatekeeper mutant variants of FGFR4 kinase were reported. The representative compound 10z exhibited potent activity and antiproliferative activity against HCC cells.
The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhib-itors 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.

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