Issue 1, 2012
From the journal:

MedChemComm

Structure–activity relationships of methyl-lysine reader antagonists†‡

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

* Corresponding authors

a Center for Integrated Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, Division of Medicinal Chemistry and Natural Products, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
E-mail: svfrye@email.unc.edu
Fax: +1 919-843-8465
Tel: +1 919-843-5486

b Department of Biology, Stanford University, Stanford, California, United States
Fax: +1 650-725-8309
Tel: +1 650-736-7639

c Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

Abstract

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 histoneprotein-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.

Graphical abstract: Structure–activity relationships of methyl-lysine reader antagonists

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Article information

DOI
https://doi.org/10.1039/C1MD00195G
Article type
Concise Article
Submitted
29 Jul 2011
Accepted
13 Sep 2011
First published
10 Oct 2011

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

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Structure–activity relationships of methyl-lysine reader antagonists

J. M. Herold, L. I. James, V. K. Korboukh, C. Gao, K. E. Coil, D. J. Bua, J. L. Norris, D. B. Kireev, P. J. Brown, J. Jin, W. P. Janzen, O. Gozani and S. V. Frye, Med. Chem. Commun., 2012, 3, 45 DOI: 10.1039/C1MD00195G

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