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

  • J Med Chem. 2022 Nov 10;65(21):14809-14831. doi: 10.1021/acs.jmedchem.2c01319.
Fang Yang  1 ,  Xiaojuan Chen  2 ,  Xiaojuan Song  1 ,  Raquel Ortega  3 ,  Xiaojing Lin  3 ,  Wuqing Deng  1 ,  Jing Guo  1 ,  Zhengchao Tu  1 ,  Adam V Patterson  3  4 ,  Jeff B Smaill  3  4 ,  Yongheng Chen  2 ,  Xiaoyun Lu  1
Affiliations
  • 1. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
  • 2. Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 3. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 4. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
PMID: 36278929 DOI: 10.1021/acs.jmedchem.2c01319
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.

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