GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
J Med Chem. 2020 Sep 10;63(17):9020-9044. doi: 10.1021/acs.jmedchem.0c00566. Epub 2020 Aug 3.
The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.
溴结构域和末端结构域（BET）表观遗传调控家族包含四个蛋白（BRD2、BRD3、BRD4、BRDT），每个蛋白都包含串联的溴结构域。迄今为止，这些蛋白的小分子抑制剂通常以相似的亲和力结合家族的所有八个溴结构域，从而产生多种生物学效应。为了进一步了解泛 BET 抑制的广泛表型特征，需要开发针对家族内个别或多组溴结构域的抑制剂。在这方面，我们报告了一种强效探针分子的发现，该分子对 BET 的 N 端溴结构域（BD1）比对 C 端溴结构域（BD2）具有高达 150 倍的选择性。基于结构信息，针对 BD1 和 BD2 结构域之间的特定氨基酸差异进行了靶向，以与先前开发的 I-BET151 支架上附加的化学功能进行选择性相互作用。本文提供的数据表明，BD1 结构域的选择性抑制足以驱动抗炎和抗增殖作用。
