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

Justin M Rectenwald,Stephen V Frye,Kyle W Kaufmann,Yi-En Liao,Dmitri B Kireev,Shiva Krishna Reddy Guduru,Jacqueline L Norris-Drouin,Scott M Hammond,Zhao Dang,Stephanie H Cholensky,Leonard B Collins,Kenneth H Pearce

doi:10.3390/molecules25040979

Justin M Rectenwald, Stephen V Frye + Show 10 more

Open Access

https://doi.org/10.3390/molecules25040979

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Abstract

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.

Highlights

One mechanism for the modulation of chromatin structure and dynamics is through post-translational modifications (PTMs) on the N-terminal tails of histone proteins found in nucleosomes.The biological consequences associated with PTMs result from recruitment of regulatory complexes through “reader” domains that recognize them, either individually, or in combination
We have been utilizing a target class platform for Kme reader proteins and have gained insight into the types of molecules that bind to Kme readers [53,56,62,63,64]
A focused DNA-Encoded Library (DEL) screening platform is an attractive option for hit discovery within a specific target class

Summary

Introduction

One mechanism for the modulation of chromatin structure and dynamics is through post-translational modifications (PTMs) on the N-terminal tails of histone proteins found in nucleosomes.The biological consequences associated with PTMs result from recruitment of regulatory complexes through “reader” domains that recognize them, either individually, or in combination. One mechanism for the modulation of chromatin structure and dynamics is through post-translational modifications (PTMs) on the N-terminal tails of histone proteins found in nucleosomes. Molecules 2020, 25, 979 interactions with PTMs are being revealed regularly with many of these proteins containing at least two adjacent methyl-lysine (Kme) reader domains [3,4,5,6,7,8,9]. These multivalent proteins are of therapeutic interest due to their association with numerous human diseases (Table 1)

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