Structure–activity relationships of methyl-lysine reader antagonists

J. Martin Herold; Lindsey Ingerman James; Victoria K. Korboukh; Cen Gao; Kaitlyn E. Coil; Dennis J. Bua; Jacqueline L. Norris; Dmitri B. Kireev; Peter J. Brown; Jian Jin; William P. Janzen; Or Gozani; Stephen V. Frye

doi:10.1039/C1MD00195G

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MedChemComm

Issue 1, 2012

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Structure–activity relationships of methyl-lysine reader antagonists

J. Martin Herold , Lindsey Ingerman James , Victoria K. Korboukh , Cen Gao , Kaitlyn E. Coil , Dennis J. Bua , Jacqueline L. Norris , Dmitri B. Kireev , Peter J. Brown , Jian Jin , William P. Janzen , Or Gozani and Stephen V. Frye

Med. Chem. Commun., 2012,3, 45-51

DOI: 10.1039/C1MD00195G
Received 29 Jul 2011, Accepted 13 Sep 2011
First published on the web 10 Oct 2011
This article is part of the collection: Epigenetics

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The interaction between methyl-lysine binding proteins and methylated histones plays a crucial role in the regulation of gene expression. Herein we describe the development of structure–activity relationships (SAR) surrounding UNC669, the first reported small molecule ligand for a methyl-lysine binding domain, using multiple assay formats. These studies revealed the key features required for successful inhibition of the L3MBTL1-methylated histone protein-protein interaction, while the selectivity of designed compounds against a panel of related methyl-lysine readers was also evaluated. Additionally, an optimized compound was demonstrated to successfully inhibit the recognition of H4K20me1 by L3MBTL1 in the context of an affinity pull down assay.