2. Academic Validation
  3. Structure-Based Design of 4-(1-Methyl-1 H-indol-3-yl)pyrimidin-2-amine Derivatives as the First Covalent FGFR3 Selective Inhibitors

Structure-Based Design of 4-(1-Methyl-1 H-indol-3-yl)pyrimidin-2-amine Derivatives as the First Covalent FGFR3 Selective Inhibitors

  • J Med Chem. 2026 Mar 12;69(5):5199-5218. doi: 10.1021/acs.jmedchem.5c02552.
Wenjian Zhu 1,  Xiaojuan Chen 2,  Xiaofei Li 1,  Jieying Lin 1,  Xiaojing Lin 3,  Xueru Liu 2,  Wuqing Deng 1,  Xiaojuan Song 1,  Zhengchao Tu 1,  Adam V Patterson 3,  Jeff B Smaill 3,  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 1142, New Zealand.
PMID: 41648938 DOI: 10.1021/acs.jmedchem.5c02552
Abstract

Aberrant Fibroblast Growth Factor receptor 3 (FGFR3) activation drives bladder carcinogenesis in humans, but currently approved pan-FGFR inhibitors lack FGFR3 isoform selectivity and fail to counter clinically acquired resistance mutations (e.g., FGFR3 V555M/L). Herein, we report the structure-based drug design of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives as the first covalent FGFR3 selective inhibitors. The representative compound 10s displayed high potency against FGFR3 (IC50 = 6.8 nM) and 5-60-fold selectivity over FGFR1/2/4. It was also effective against the common clinically acquired FGFR3V555M resistance mutation with an IC50 value of 19.2 nM. Furthermore, 10s exhibited strong antiproliferative effects in FGFR3-driven RT112/84 cells (IC50 = 9.2 nM). Structural characterization using MALDI-TOF-MS and X-ray crystallography confirmed covalent binding of 10s to FGFR3. Compound 10s also showed significant antitumor efficacy in the RT112/84 bladder Cancer xenograft model, offering a promising compound to address both selectivity and resistance in FGFR3-targeted therapy.

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