Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins

Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that 'read...

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Published in:	Molecules (Basel, Switzerland) Vol. 25; no. 4; p. 979
Main Authors:	Rectenwald, Justin M, Guduru, Shiva Krishna Reddy, Dang, Zhao, Collins, Leonard B, Liao, Yi-En, Norris-Drouin, Jacqueline L, Cholensky, Stephanie H, Kaufmann, Kyle W, Hammond, Scott M, Kireev, Dmitri B, Frye, Stephen V, Pearce, Kenneth H
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 22-02-2020 MDPI
Subjects:	Binding sites Cellular structure Chromatin Chromatin - chemistry Chromatin - genetics Chromatin Assembly and Disassembly - genetics chromatin reader protein Communication Complex systems Computer applications Construction Deoxyribonucleic acid DNA DNA - chemistry DNA - genetics DNA methylation DNA probes dna-encoded libraries Domains Epigenome Gene Library Histones - genetics Humans Kinases Ligands Lysine Lysine - chemistry Lysine - genetics Optimization Organic chemistry Phenotypes Post-translation Protein Binding - genetics Protein Processing, Post-Translational - genetics Proteins Structure-function relationships Success target-class drug discovery target-class drug discovery DNA-Encoded Libraries chromatin reader protein
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Summary:	Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that 'read' these PTMs. High-quality chemical probes that can block reader functions of proteins involved in chromatin regulation are important tools to improve our understanding of pathways involved in chromatin dynamics. Insight into the intricate system of chromatin PTMs and their context within the epigenome is also therapeutically important as misregulation of this complex system is implicated in numerous human diseases. Using computational methods, along with structure-based knowledge, we have designed and constructed a focused DNA-Encoded Library (DEL) containing approximately 60,000 compounds targeting bi-valent methyl-lysine (Kme) reader domains. Additionally, we have constructed DNA-barcoded control compounds to allow optimization of selection conditions using a model Kme reader domain. We anticipate that this target-class focused approach will serve as a new method for rapid discovery of inhibitors for multivalent chromatin reader domains.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules25040979