Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4md00274a.
G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulationviathe 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 observedin vitrodata.
Department of Chemistry , Imperial College London , London SW7 2AZ , UK . Email: m. fuchter@imperial.ac.uk ; ; Tel: +44 (0)2075945815 ; Institute of Chemical Biology , Imperial College London , London SW7 2AZ , UK.
Nitipol
N
Srimongkolpithak
Department of Chemistry , Imperial College London , London SW7 2AZ , UK . Email: m. fuchter@imperial.ac.uk ; ; Tel: +44 (0)2075945815.
Sandeep
S
Sundriyal
Structural Genomics Consortium , University of Toronto , Toronto , Ontario M5G 1L7 , Canada.
Fengling
F
Li
Structural Genomics Consortium , University of Toronto , Toronto , Ontario M5G 1L7 , Canada.
Masoud
M
Vedadi
Department of Chemistry , Imperial College London , London SW7 2AZ , UK . Email: m. fuchter@imperial.ac.uk ; ; Tel: +44 (0)2075945815.
Matthew J
MJ
Fuchter