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
UNC School of Medicine, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
UNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Molecules. 2020 Feb 22;25(4):979. doi: 10.3390/molecules25040979.
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.
染色质结构和功能，进而细胞表型，部分受染色质修饰酶网络的调控，这些酶在组蛋白尾部进行翻译后修饰（PTM）。这些标记作为其他“读取”这些PTM的染色质调节复合物的招募位点。能够阻断参与染色质调节的蛋白质读取功能的高质量化学探针是增进我们对染色质动力学相关途径理解的重要工具。深入了解染色质PTM的复杂系统及其在表观基因组中的背景在治疗方面也很重要，因为这个复杂系统的失调与多种人类疾病有关。利用计算方法以及基于结构的知识，我们设计并构建了一个聚焦的DNA编码文库（DEL），其中包含约60,000种靶向双价甲基赖氨酸（Kme）读取结构域的化合物。此外，我们构建了DNA条形码对照化合物，以便使用模型Kme读取结构域优化选择条件。我们预计这种针对目标类别的方法将成为快速发现多价染色质读取结构域抑制剂的新方法。
