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Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors
Neratinib is an oral pan HER inhibitor, that irreversibly inhibits EGFR and HER2 and was proven to be effective against multiple EGFR mutations. In previous study, we reported spiro [indoline-3, 4′-piperidine]-2-ones as anticancer agents. In this study, we designed aminopyridine-containing spiro [in...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691816/ https://www.ncbi.nlm.nih.gov/pubmed/31286784 http://dx.doi.org/10.1080/14756366.2019.1634704 |
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author | Ye, Lianbao Zhao, Tao Du, Wenjun Li, Anhu Gao, Wei Li, Jingrong Wang, Ling Chen, Weiqiang |
author_facet | Ye, Lianbao Zhao, Tao Du, Wenjun Li, Anhu Gao, Wei Li, Jingrong Wang, Ling Chen, Weiqiang |
author_sort | Ye, Lianbao |
collection | PubMed |
description | Neratinib is an oral pan HER inhibitor, that irreversibly inhibits EGFR and HER2 and was proven to be effective against multiple EGFR mutations. In previous study, we reported spiro [indoline-3, 4′-piperidine]-2-ones as anticancer agents. In this study, we designed aminopyridine-containing spiro [indoline-3,4′-piperidine] derivatives A1-A4 using Neratinib and spiro [indoline-3, 4′-piperidine]-2-one compound patented as lead structure, then replaced piperidine with cyclopropane to obtain B1-B7 and replaced indoline with benzmorpholine to get C1-C4 and D1-D2. We synthesized these compounds and evaluated their residual activities under 0.5 M drug concentration on EGFR and ERBB2. Most of compounds showed stronger inhibition on EGFR-wt and ERBB2, in which A1-A4 showed excellent inhibitory activity with inhibition percentage on EGFR-wt kinase of 7%, 6%, 19%, 27%, respectively and 9%, 5%, 12%, 34% on ERBB2 kinase compared with 2% and 6% of Neratinib. |
format | Online Article Text |
id | pubmed-6691816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-66918162019-08-23 Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors Ye, Lianbao Zhao, Tao Du, Wenjun Li, Anhu Gao, Wei Li, Jingrong Wang, Ling Chen, Weiqiang J Enzyme Inhib Med Chem Research Paper Neratinib is an oral pan HER inhibitor, that irreversibly inhibits EGFR and HER2 and was proven to be effective against multiple EGFR mutations. In previous study, we reported spiro [indoline-3, 4′-piperidine]-2-ones as anticancer agents. In this study, we designed aminopyridine-containing spiro [indoline-3,4′-piperidine] derivatives A1-A4 using Neratinib and spiro [indoline-3, 4′-piperidine]-2-one compound patented as lead structure, then replaced piperidine with cyclopropane to obtain B1-B7 and replaced indoline with benzmorpholine to get C1-C4 and D1-D2. We synthesized these compounds and evaluated their residual activities under 0.5 M drug concentration on EGFR and ERBB2. Most of compounds showed stronger inhibition on EGFR-wt and ERBB2, in which A1-A4 showed excellent inhibitory activity with inhibition percentage on EGFR-wt kinase of 7%, 6%, 19%, 27%, respectively and 9%, 5%, 12%, 34% on ERBB2 kinase compared with 2% and 6% of Neratinib. Taylor & Francis 2019-07-09 /pmc/articles/PMC6691816/ /pubmed/31286784 http://dx.doi.org/10.1080/14756366.2019.1634704 Text en © 2019 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 Paper Ye, Lianbao Zhao, Tao Du, Wenjun Li, Anhu Gao, Wei Li, Jingrong Wang, Ling Chen, Weiqiang Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors |
title | Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors |
title_full | Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors |
title_fullStr | Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors |
title_full_unstemmed | Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors |
title_short | Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors |
title_sort | discovery of aminopyridine-containing spiro derivatives as egfr mutations inhibitors |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691816/ https://www.ncbi.nlm.nih.gov/pubmed/31286784 http://dx.doi.org/10.1080/14756366.2019.1634704 |
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