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Issue 6, 2020
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Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents

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Abstract

Zeste enhancer homolog 2 (EZH2) is highly expressed in various malignant tumors, which could silence tumor suppressor genes via trimethylation of H3K27. Herein was first reported a novel series of pyrrole-3-carboxamide derivatives carrying a pyridone fragment as EZH2 inhibitors. By combining computational modeling, in vitro cellular assays and further rational structure–activity relationship exploration and optimization, compound DM-01 showed powerful inhibition towards EZH2. DM-01 was found to have significant ability to reduce the cellular H3K27me3 level in K562 cells in the Western blot test. Meanwhile, our data showed that knockdown EZH2 in A549 cells resulted in a decrease of cell sensitivity to DM-01 at 50 and 100 μM. DM-01 could also increase the transcription expression of DIRAS3 in a dose-dependent manner, a tumor suppressor in the downstream of EZH2, suggesting it was worth investigating further as a lead compound.

Graphical abstract: Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents

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Supplementary files

Article information


Submitted
14 Sep 2019
Accepted
09 Jan 2020
First published
10 Jan 2020

New J. Chem., 2020,44, 2247-2255
Article type
Paper

Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents

Q. Zhou, L. Jia, F. Du, X. Dong, W. Sun, L. Wang and G. Chen, New J. Chem., 2020, 44, 2247
DOI: 10.1039/C9NJ04713A

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