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Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors

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journal contribution
posted on 2020-04-27, 09:53 authored by Daseul Im, Hyungwoo Moon, Jinwoong Kim, Youri Oh, Miyoung Jang, Jung-Mi Hah

A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC50= 106 nM) with excellent selectivity profiles over 36 other protein kinases including cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC50 value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics.

Funding

This work was financially supported by grants from the National Research Foundation of Korea [NRF-2017R1A2B4006447 and NRF-2019M3A9A8066500; J.-M. Hah].

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