2. Academic Validation
  3. Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors

Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors

  • Eur J Med Chem. 2024 Jun 9:275:116558. doi: 10.1016/j.ejmech.2024.116558.
Wuqing Deng 1,  Xiaojuan Chen 2,  Hong Liang 1,  Xiaojuan Song 1,  Shuang Xiang 1,  Jing Guo 1,  Zhengchao Tu 1,  Yang Zhou 3,  Yongheng Chen 4,  Xiaoyun Lu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, 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 State Key Laboratory of Bioactive Molecules and Druggability Assessment, 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. Electronic address: zhouyang@jnu.edu.cn.
  • 4 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. Electronic address: yonghenc@163.com.
  • 5 State Key Laboratory of Bioactive Molecules and Druggability Assessment, 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; Department of Hematology, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, 510632, China. Electronic address: luxy2016@jnu.edu.cn.
PMID: 38870833 DOI: 10.1016/j.ejmech.2024.116558
Abstract

The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC50 = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung Cancer cells, SNU-16 and KATO III gastric Cancer cells with IC50 values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for Anticancer drug development medicated by FGFRs.

Keywords

5-Amino-1H-pyrazole-4-carboxamide; Covalent binding; Gatekeeper mutation; Pan-FGFR inhibitors; Structure-based drug design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162577
    FGFR Inhibitor