Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
Curr Opin Chem Biol. 2021 Aug;63:132-144. doi: 10.1016/j.cbpa.2021.03.002. Epub 2021 Apr 11.
Responsible for interpreting histone post-translational modifications, epigenetic reader proteins have emerged as novel therapeutic targets for a wide range of diseases. Chemical probes have been critical in enabling target validation studies and have led to translational advances in cancer and inflammation-related pathologies. Here, we present the most recently reported probes of reader proteins that recognize acylated and methylated lysine. We will discuss challenges associated with achieving potent antagonism of reader domains and review ongoing efforts to overcome these hurdles, focusing on targeting strategies including the use of peptidomimetic ligands, allosteric modulators, and protein degraders.
负责解释组蛋白翻译后修饰的表观遗传读蛋白已成为多种疾病的新型治疗靶点。化学探针在实现靶标验证研究方面至关重要，并推动了癌症和炎症相关病理的转化进展。在这里，我们介绍了最近报道的识别酰化和甲基化赖氨酸的读蛋白探针。我们将讨论实现读蛋白结构域有效拮抗所面临的挑战，并回顾克服这些障碍的持续努力，重点关注包括使用肽模拟配体、别构调节剂和蛋白降解剂在内的靶向策略。
