Current Chemical Genomics and Translational Medicine

2011, 5 : 51-61
Published online 2011 August 22. DOI: 10.2174/1875397301005010051
Publisher ID: CCGTM-5-51

RESEARCH ARTICLE
 Drug Discovery Toward Antagonists of Methyl-Lysine Binding Proteins

J. Martin Herold , Lindsey A Ingerman , Cen Gao and Stephen V Frye, *
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 27599, USA

* Address correspondence to this author at the 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 27599, USA; Tel: 919-843-5486; Fax: 919-843-8465; E-mail: svfrye@email.unc.edu

ABSTRACT

The recognition of methyl-lysine and -arginine residues on both histone and other proteins by specific “reader” elements is important for chromatin regulation, gene expression, and control of cell-cycle progression. Recently the crucial role of these reader proteins in cancer development and dedifferentiation has emerged, owing to the increased interest among the scientific community. The methyl-lysine and -arginine readers are a large and very diverse set of effector proteins and targeting them with small molecule probes in drug discovery will inevitably require a detailed understanding of their structural biology and mechanism of binding. In the following review, the critical elements of methyl-lysine and -arginine recognition will be summarized with respect to each protein family and initial results in assay development, probe design, and drug discovery will be highlighted.

Keywords:

Histones, chromatin, chemical probes, reader domains, methyl-lysine, methyl-arginine, post-translational modifications, pi-cation interactions, drug discovery.