2. Academic Validation
  3. Design, Synthesis and Biological Evaluation of 7-(1-Methyl-1 H-indole-3-yl)-5 H-pyrrolo[2,3- b]pyrazine Derivatives as Novel Covalent pan-FGFR Inhibitors to Overcome Clinical Resistance

Design, Synthesis and Biological Evaluation of 7-(1-Methyl-1 H-indole-3-yl)-5 H-pyrrolo[2,3- b]pyrazine Derivatives as Novel Covalent pan-FGFR Inhibitors to Overcome Clinical Resistance

  • J Med Chem. 2025 Sep 25;68(18):19415-19437. doi: 10.1021/acs.jmedchem.5c01594.
Wuqing Deng 1,  Xiaojuan Chen 2,  Ling Yan 1,  Shuang Xiang 1,  Xiaojuan Song 1,  Lin Zhang 2,  Xiaofei Li 1,  Wenjian Zhu 1,  Junping Pei 1,  Xiaojing Lin 3,  Adam V Patterson 3,  Jeff B Smaill 3,  Bingsheng Li 4,  Zhengchao Tu 1,  Yang Zhou 1,  Yongheng Chen 2,  Xiaoyun Lu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 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, Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag, 92019 Auckland, New Zealand.
  • 4 Department of Gastroenterology, Huizhou First Hospital, Huizhou 516000, China.
PMID: 40921092 DOI: 10.1021/acs.jmedchem.5c01594
Abstract

Aberrant activation of Fibroblast Growth Factor receptors (FGFRs) plays a critical role in tumorigenesis across multiple Cancer types, driving the development of various FGFR inhibitors. Despite clinical advances, therapeutic efficacy remains limited by the emergence of drug resistance, primarily mediated by gatekeeper mutations in FGFRs. To overcome this challenge, we designed and synthesized a novel series of 7-(1-methyl-1H-indole-3-yl)-5H-pyrrolo[2,3-b]pyrazine derivatives as covalent pan-FGFR inhibitors targeting both wild-type and gatekeeper mutants. Compound 9p demonstrated potent nanomolar inhibitory activity against FGFR1-3 and gatekeeper mutants in biochemical and cellular assays. Structural characterization using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) and X-ray crystallography confirmed covalent binding of 9p to FGFR1. Additionally, 9p showed significant in vivo antitumor efficacy in nude mice bearing the RT112 bladder Cancer xenograft model. These findings establish 9p as a promising lead for further development of FGFR-targeted Anticancer therapies.

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