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Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors

Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series o...

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Autores principales: Hao, Yongjia, Lyu, Jiankun, Qu, Rong, Sun, Deheng, Zhao, Zhenjiang, Chen, Zhuo, Ding, Jian, Xie, Hua, Xu, Yufang, Li, Honglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476563/
https://www.ncbi.nlm.nih.gov/pubmed/28630494
http://dx.doi.org/10.1038/s41598-017-04184-9
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author Hao, Yongjia
Lyu, Jiankun
Qu, Rong
Sun, Deheng
Zhao, Zhenjiang
Chen, Zhuo
Ding, Jian
Xie, Hua
Xu, Yufang
Li, Honglin
author_facet Hao, Yongjia
Lyu, Jiankun
Qu, Rong
Sun, Deheng
Zhao, Zhenjiang
Chen, Zhuo
Ding, Jian
Xie, Hua
Xu, Yufang
Li, Honglin
author_sort Hao, Yongjia
collection PubMed
description Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR(L858R/T790M) (H1975 cell lines) over EGFR(WT) (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFR(L858R/T790M). These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.
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spelling pubmed-54765632017-06-23 Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors Hao, Yongjia Lyu, Jiankun Qu, Rong Sun, Deheng Zhao, Zhenjiang Chen, Zhuo Ding, Jian Xie, Hua Xu, Yufang Li, Honglin Sci Rep Article Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR(L858R/T790M) (H1975 cell lines) over EGFR(WT) (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFR(L858R/T790M). These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer. Nature Publishing Group UK 2017-06-19 /pmc/articles/PMC5476563/ /pubmed/28630494 http://dx.doi.org/10.1038/s41598-017-04184-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hao, Yongjia
Lyu, Jiankun
Qu, Rong
Sun, Deheng
Zhao, Zhenjiang
Chen, Zhuo
Ding, Jian
Xie, Hua
Xu, Yufang
Li, Honglin
Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors
title Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors
title_full Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors
title_fullStr Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors
title_full_unstemmed Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors
title_short Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors
title_sort structure-guided design of c4-alkyl-1,4-dihydro-2h-pyrimido[4,5-d][1,3]oxazin-2-ones as potent and mutant-selective epidermal growth factor receptor (egfr) l858r/t790m inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476563/
https://www.ncbi.nlm.nih.gov/pubmed/28630494
http://dx.doi.org/10.1038/s41598-017-04184-9
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