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

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-methylpipe...

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Autores principales: Im, Daseul, Moon, Hyungwoo, Kim, Jinwoong, Oh, Youri, Jang, Miyoung, Hah, Jung-Mi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Short Communication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241567/
https://www.ncbi.nlm.nih.gov/pubmed/32338093
http://dx.doi.org/10.1080/14756366.2020.1758689
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author Im, Daseul
Moon, Hyungwoo
Kim, Jinwoong
Oh, Youri
Jang, Miyoung
Hah, Jung-Mi
author_facet Im, Daseul
Moon, Hyungwoo
Kim, Jinwoong
Oh, Youri
Jang, Miyoung
Hah, Jung-Mi
author_sort Im, Daseul
collection PubMed
description 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 (IC(50)= 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 IC(50) value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics.
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spelling pubmed-72415672020-06-01 Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors Im, Daseul Moon, Hyungwoo Kim, Jinwoong Oh, Youri Jang, Miyoung Hah, Jung-Mi J Enzyme Inhib Med Chem Short Communication 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 (IC(50)= 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 IC(50) value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics. Taylor & Francis 2020-04-27 /pmc/articles/PMC7241567/ /pubmed/32338093 http://dx.doi.org/10.1080/14756366.2020.1758689 Text en © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Communication
Im, Daseul
Moon, Hyungwoo
Kim, Jinwoong
Oh, Youri
Jang, Miyoung
Hah, Jung-Mi
Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors
title Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors
title_full Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors
title_fullStr Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors
title_full_unstemmed Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors
title_short Discovery of 5-methyl-N-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective FLT3 inhibitors
title_sort discovery of 5-methyl-n-(2-arylquinazolin-7-yl)isoxazole-4-carboxamide analogues as highly selective flt3 inhibitors
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241567/
https://www.ncbi.nlm.nih.gov/pubmed/32338093
http://dx.doi.org/10.1080/14756366.2020.1758689
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