Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors

A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).近期已有多项研究成果发表，报道了针对第二个溴域（BD2）具有选择性的溴域及额外末端结构域抑制剂的发现与优化工作，其中涵盖了本团队针对GSK046（3）与GSK620（5）所开展的相关研究。本文详细阐述了我们通过将乙酰胺官能团替换为杂环，以降低GSK046遗传毒性风险的研究方案。在此基础上，我们以基于结构的药物设计为指导，采用模板跳转与杂交策略，整合其他BD2选择性抑制剂系列的研究成果，优化酰胺区域的分子骨架，并探索ZA裂隙，最终成功筛选得到兼具强效活性、高选择性与良好生物可利用性的化合物28（GSK452）、39（GSK737）与36（GSK217）。