The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.

中文翻译：

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发现了8-甲基-吡咯并[1,2-a]吡嗪-1（2H）-one衍生物作为高活性和选择性溴结构域和末端（BET）溴结构域抑制剂。

溴结构域和末端外（BET）家族蛋白最近已成为有希望的癌症治疗药物靶标。在这项研究中，鉴定了一个8-甲基-吡咯并[1,2-a]吡嗪-1（2H）-一个片段（47）作为BET溴结构域的新结合物，随后将片段47掺入了该载体的支架中。最近进入I期临床试验的ABBV-075使能够产生一系列高效的BET溴结构域抑制剂。进一步的可药物性优化导致发现化合物38作为潜在的临床前候选药物。值得注意的是，与ABBV-075相比，BBB4（1）对BRD4（1）的选择性是EP300的63倍，化合物38对BET溴结构域家族的选择性比其他溴结构域好，而BRD4（1）的选择性约为1500倍。超过EP300。