Runcie Andrew C, Chan Kwok-Ho, Zengerle Michael, Ciulli Alessio
School of Life Sciences, University of Dundee, Division of Biological Chemistry and Drug Discovery, James Black Centre, Dow Street, Dundee DD1 5EH, UK.
School of Life Sciences, University of Dundee, Division of Biological Chemistry and Drug Discovery, James Black Centre, Dow Street, Dundee DD1 5EH, UK.
Curr Opin Chem Biol. 2016 Aug;33:186-94. doi: 10.1016/j.cbpa.2016.06.031. Epub 2016 Jul 14.
Chemical genetics is the use of biologically active small molecules (chemical probes) to investigate the functions of gene products, through the modulation of protein activity. Recent years have seen significant progress in the application of chemical genetics to study epigenetics, following the development of new chemical probes, a growing appreciation of the role of epigenetics in disease and a recognition of the need and utility of high-quality, cell-active chemical probes. In this review, we single out the bromodomain reader domains as a prime example of both the success, and challenges facing chemical genetics. The difficulty in generating single-target selectivity has long been a thorn in the side of chemical genetics, however, recent developments in advanced forms of chemical genetics promise to bypass this, and other, limitations. The 'bump-and-hole' approach has now been used to probe - for the first time - the BET bromodomain subfamily with single-target selectivity and may be applicable to other epigenetic domains. Meanwhile, PROTAC compounds have been shown to be significantly more efficacious than standard domain inhibitors, and have the potential to enhance target selectivity.
化学遗传学是利用具有生物活性的小分子（化学探针），通过调节蛋白质活性来研究基因产物的功能。近年来，随着新型化学探针的开发、对表观遗传学在疾病中作用的日益重视以及对高质量、具有细胞活性的化学探针的需求和实用性的认识，化学遗传学在研究表观遗传学方面取得了显著进展。在本综述中，我们将溴结构域阅读结构域作为化学遗传学成功与面临挑战的一个主要例子。长期以来，产生单靶点选择性的困难一直是化学遗传学的一大难题，然而，先进形式的化学遗传学的最新进展有望绕过这一以及其他限制。“凸起-孔洞”方法现已首次用于以单靶点选择性探测BET溴结构域亚家族，并且可能适用于其他表观遗传结构域。与此同时，蛋白水解靶向嵌合体（PROTAC）化合物已被证明比标准结构域抑制剂更有效，并且具有提高靶点选择性的潜力。
