Biophysics Program, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT 06511, USA.
Future Med Chem. 2020 Jul;12(14):1305-1326. doi: 10.4155/fmc-2020-0082. Epub 2020 Jun 19.
Epigenetic protein-protein interactions (PPIs) play essential roles in regulating gene expression, and their dysregulations have been implicated in many diseases. These PPIs are comprised of reader domains recognizing post-translational modifications on histone proteins, and of scaffolding proteins that maintain integrities of epigenetic complexes. Targeting PPIs have become focuses for development of small-molecule inhibitors and anticancer therapeutics. Here we summarize efforts to develop small-molecule inhibitors targeting common epigenetic PPI domains. Potent small molecules have been reported for many domains, yet small domains that recognize methylated lysine side chains on histones are challenging in inhibitor development. We posit that the development of potent inhibitors for difficult-to-prosecute epigenetic PPIs may be achieved by interdisciplinary approaches and extensive explorations of chemical space.
表观遗传蛋白-蛋白相互作用 (PPIs) 在调节基因表达中起着至关重要的作用，其失调与许多疾病有关。这些 PPIs 由识别组蛋白翻译后修饰的读取结构域和维持表观遗传复合物完整性的支架蛋白组成。靶向 PPI 已成为开发小分子抑制剂和抗癌治疗药物的重点。在这里，我们总结了开发针对常见表观遗传 PPI 结构域的小分子抑制剂的努力。已经报道了许多结构域的有效小分子，然而识别组蛋白上甲基化赖氨酸侧链的小结构域在抑制剂开发中具有挑战性。我们认为，通过跨学科方法和广泛探索化学空间，可能开发出针对难以进行的表观遗传 PPI 的有效抑制剂。
