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

Authors :: Kuriwaki I
Kameda M
Hisamichi H
Kikuchi S
Iikubo K
Kawamoto Y
Moritomo H
Kondoh Y
Amano Y
Tateishi Y
Echizen Y
Iwai Y
Noda A
Tomiyama H
Suzuki T
Hirano M
Source :: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 May 15; Vol. 28 (10), pp. 115453. Date of Electronic Publication: 2020 Mar 28.
Publication Year :: 2020
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.<br />Competing Interests: Declaration of Competing Interest This research is a collaboration between Astellas Pharma Inc. and Kotobuki Pharmaceutical Co., Ltd.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Subjects :: Cell Line
Dose-Response Relationship, Drug
Humans
Molecular Structure
Protein Kinase Inhibitors chemistry
Pyrimidines chemistry
Receptor, Fibroblast Growth Factor, Type 3 metabolism
Structure-Activity Relationship
Triazines chemistry
Vascular Endothelial Growth Factor Receptor-2 metabolism
Drug Design
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Receptor, Fibroblast Growth Factor, Type 3 antagonists & inhibitors
Triazines pharmacology
Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors

Full Text Access

Tools