Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors

G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemoty...

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Autores principales: Srimongkolpithak, Nitipol, Sundriyal, Sandeep, Li, Fengling, Vedadi, Masoud, Fuchter, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2014
Materias:
Chemistry
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349132/
https://www.ncbi.nlm.nih.gov/pubmed/25750706
http://dx.doi.org/10.1039/c4md00274a
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author Srimongkolpithak, Nitipol
Sundriyal, Sandeep
Li, Fengling
Vedadi, Masoud
Fuchter, Matthew J.
author_facet Srimongkolpithak, Nitipol
Sundriyal, Sandeep
Li, Fengling
Vedadi, Masoud
Fuchter, Matthew J.
author_sort Srimongkolpithak, Nitipol
collection PubMed
description G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data.
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spelling pubmed-43491322015-03-05 Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors Srimongkolpithak, Nitipol Sundriyal, Sandeep Li, Fengling Vedadi, Masoud Fuchter, Matthew J. Medchemcomm Chemistry G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data. Royal Society of Chemistry 2014-12-19 2014-09-11 /pmc/articles/PMC4349132/ /pubmed/25750706 http://dx.doi.org/10.1039/c4md00274a Text en This journal is © The Royal Society of Chemistry 2014 http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemistry
Srimongkolpithak, Nitipol
Sundriyal, Sandeep
Li, Fengling
Vedadi, Masoud
Fuchter, Matthew J.
Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
title Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
title_full Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
title_fullStr Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
title_full_unstemmed Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
title_short Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
title_sort identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as g9a inhibitors
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349132/
https://www.ncbi.nlm.nih.gov/pubmed/25750706
http://dx.doi.org/10.1039/c4md00274a
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