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).

近期已有多篇学术文献报道了对第二个溴结构域（BD2）具有选择性的溴域与额外末端结构域抑制剂（bromo and extraterminal inhibitors）的发现与优化研究，其中包括本团队针对GSK046（编号3）与GSK620（编号5）开展的相关工作。本文详述了本团队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策略。在此基础上，本团队在基于结构的药物设计指导下，采用模板跳跃与杂交策略，整合其他BD2选择性抑制剂系列的研究经验，优化酰胺区域的连接臂，并探索ZA裂隙，最终成功鉴定出强效、高选择性且具备良好生物利用度的化合物28（GSK452）、39（GSK737）与36（GSK217）。