2. Academic Validation
  3. Synthesis, biological evaluation, QSAR and molecular dynamics simulation studies of potential fibroblast growth factor receptor 1 inhibitors for the treatment of gastric cancer

Synthesis, biological evaluation, QSAR and molecular dynamics simulation studies of potential fibroblast growth factor receptor 1 inhibitors for the treatment of gastric cancer

  • Eur J Med Chem. 2017 Feb 15:127:885-899. doi: 10.1016/j.ejmech.2016.10.066.
Shilong Ying 1,  Xiaojing Du 2,  Weitao Fu 1,  Di Yun 1,  Liping Chen 1,  Yuepiao Cai 1,  Qing Xu 3,  Jianzhang Wu 4,  Wulan Li 5,  Guang Liang 1
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China; Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 323000, China.
  • 3 College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, China.
  • 4 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China. Electronic address: wjzwzmu@163.com.
  • 5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical Universtiy, Wenzhou, Zhejiang 325035, China; College of Information Science and Computer Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: lwlwzmu@163.com.
PMID: 27829519 DOI: 10.1016/j.ejmech.2016.10.066
Abstract

Accumulating evidence suggests that Fibroblast Growth Factor receptor 1 (FGFR1) is an attractive target in gastric Cancer therapy. Based on our previous discovery of two non-ATP competitive FGFR1 inhibitors, A114 and A117, we designed and screened a series of compounds with the framework of bisaryl-1,4-dien-3-one. Among them, D12 and D15 exhibited the most potent FGFR1 inhibitory activity, which was ATP-independent. Furthermore, a quantitative structure-activity relationship analysis of 41 analogs demonstrated that the specific structural substitutions alter their bioactivities. Molecular docking and dynamics simulation analysis indicated the hydrophobic interaction at the FGFR1-D12/D15 interaction was dominant. Evaluation for anti-gastric Cancer efficacy of D12 and D15 indicated effective inhibition of cell proliferation, Apoptosis induction and cell cycle arrest. Thus, these two FGFR1 inhibitors have therapeutic potential in the treatment of gastric Cancer, and this study provides will contribute to the rational design of novel non-ATP competitive FGFR1 inhibitors.

Keywords

Design; Fibroblast growth factor receptor 1; Gastric cancer; Quantitative structure-activity relationship.

Figures