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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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

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

doi

10.1016/j.bmc.2020.115453

subject

Has Abstract

pub_date

2020-05-15 00:00:00

pages

115453

issue

10

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30267-4

journal_volume

28

pub_type

杂志文章

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