2. Academic Validation
  3. Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors

Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors

  • J Med Chem. 2023 Mar 9;66(5):3226-3249. doi: 10.1021/acs.jmedchem.2c01507.
Chunpu Li 1 2,  Yang Dai 3,  Xiangtai Kong 1 4,  Bao Wang 1,  Xia Peng 3,  Hengbo Wu 1 4,  Yanyan Shen 3,  Yanchen Yang 1 5,  Yinchun Ji 3,  Danyi Wang 3 4,  Shuangjie Li 1,  Xutong Li 1,  Yuqiang Shi 1,  Meiyu Geng 3 2 4 6,  Mingyue Zheng 1 2 4,  Jing Ai 3 2 4,  Hong Liu 1 2 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
  • 3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 36802596 DOI: 10.1021/acs.jmedchem.2c01507
Abstract

Small-molecule Fibroblast Growth Factor receptor (FGFR) inhibitors have emerged as a promising antitumor therapy. Herein, by further optimizing the lead compound 1 under the guidance of molecular docking, we obtained a series of novel covalent FGFR inhibitors. After careful structure-activity relationship analysis, several compounds were identified to exhibit strong FGFR inhibitory activity and relatively better physicochemical and pharmacokinetic properties compared with those of 1. Among them, 2e potently and selectively inhibited the kinase activity of FGFR1-3 wildtype and high-incidence FGFR2-N549H/K-resistant mutant kinase. Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable antiproliferative activity in FGFR-aberrant Cancer cell lines. In addition, the oral administration of 2e in the FGFR1-amplified H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models demonstrated potent antitumor efficacy, inducing tumor stasis or even tumor regression.

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