Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance

Bcr-Abl(T315I) induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-Abl(T315I) inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC(50...

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Detalles Bibliográficos
Autores principales: Lu, Xiaoyun, Zhang, Zhang, Ren, Xiaomei, Wang, Deping, Ding, Ke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2017
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010122/
https://www.ncbi.nlm.nih.gov/pubmed/28260399
http://dx.doi.org/10.1080/14756366.2016.1250757
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author Lu, Xiaoyun
Zhang, Zhang
Ren, Xiaomei
Wang, Deping
Ding, Ke
author_facet Lu, Xiaoyun
Zhang, Zhang
Ren, Xiaomei
Wang, Deping
Ding, Ke
author_sort Lu, Xiaoyun
collection PubMed
description Bcr-Abl(T315I) induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-Abl(T315I) inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC(50) values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3(WT) and Ba/F3(T315I) cells with IC(50) values of 2.2, 0.64 and 10.8 nM. Furthermore, GZD856 potently suppressed tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-Abl(T315I). Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance.
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spelling pubmed-60101222018-07-11 Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance Lu, Xiaoyun Zhang, Zhang Ren, Xiaomei Wang, Deping Ding, Ke J Enzyme Inhib Med Chem Research Article Bcr-Abl(T315I) induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-Abl(T315I) inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC(50) values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3(WT) and Ba/F3(T315I) cells with IC(50) values of 2.2, 0.64 and 10.8 nM. Furthermore, GZD856 potently suppressed tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-Abl(T315I). Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance. Taylor & Francis 2017-03-06 /pmc/articles/PMC6010122/ /pubmed/28260399 http://dx.doi.org/10.1080/14756366.2016.1250757 Text en © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group http://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/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Lu, Xiaoyun
Zhang, Zhang
Ren, Xiaomei
Wang, Deping
Ding, Ke
Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance
title Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance
title_full Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance
title_fullStr Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance
title_full_unstemmed Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance
title_short Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl(T315I) inhibitor overcoming acquired imatinib resistance
title_sort synthesis and identification of gzd856 as an orally bioavailable bcr-abl(t315i) inhibitor overcoming acquired imatinib resistance
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010122/
https://www.ncbi.nlm.nih.gov/pubmed/28260399
http://dx.doi.org/10.1080/14756366.2016.1250757
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