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Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors.

ABSTRACT: 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.

SUBMITTER: Ye L 

PROVIDER: S-EPMC6691816 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors.

Ye Lianbao L   Zhao Tao T   Du Wenjun W   Li Anhu A   Gao Wei W   Li Jingrong J   Wang Ling L   Chen Weiqiang W  

Journal of enzyme inhibition and medicinal chemistry 20191201 1

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 <b>A1-A4</b> using Neratinib and spiro [indoline-3, 4'-piperidine]-2-one compound patented as lead structure, then replaced piperidine with cyclopropane to obtain <  ...[more]

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