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Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2.

Abstract
Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.
AuthorsIkumi Kuriwaki, Minoru Kameda, Hiroyuki Hisamichi, Shigetoshi Kikuchi, Kazuhiko Iikubo, Yuichiro Kawamoto, Hiroyuki Moritomo, Yutaka Kondoh, Yasushi Amano, Yukihiro Tateishi, Yuka Echizen, Yoshinori Iwai, Atsushi Noda, Hiroshi Tomiyama, Tomoyuki Suzuki, Masaaki Hirano
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 28 Issue 10 Pg. 115453 (05 15 2020) ISSN: 1464-3391 [Electronic] England
PMID32278710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2020 Elsevier Ltd. All rights reserved.
Chemical References
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Triazines
  • FGFR3 protein, human
  • KDR protein, human
  • Receptor, Fibroblast Growth Factor, Type 3
  • Vascular Endothelial Growth Factor Receptor-2
  • pyrimidine
Topics
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors (chemistry, pharmacology)
  • Pyrimidines (chemistry, pharmacology)
  • Receptor, Fibroblast Growth Factor, Type 3 (antagonists & inhibitors, metabolism)
  • Structure-Activity Relationship
  • Triazines (chemistry, pharmacology)
  • Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)

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