Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors
Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors
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发现 8-甲基-吡咯并[1,2-a]吡嗪-1(2H)-one 衍生物作为高效、选择性溴结构域和末端 (BET) 溴结构域抑制剂
DOI：
10.1021/acs.jmedchem.9b01784
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发表时间：
2020-04-23
影响因子：
7.3
通讯作者：
Zhou, Bing
中科院分区：
文献类型：
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作者：
Li, Zizhou;Xiao, Senhao;Zhou, Bing
布罗莫结构域和额外末端（BET）家族蛋白最近已成为癌症治疗的有希望的药物靶标。在该研究中，鉴定8-甲基-吡咯并[1，2-a]吡嗪-1（2 H）-酮片段（47）作为BET溴结构域的新结合剂，随后将片段47掺入ABBV-075的支架（其最近进入I期临床试验），使得能够产生一系列高度有效的BET溴结构域抑制剂。进一步的可药用性优化导致发现化合物38作为潜在的临床前候选物。值得注意的是，与ABBV-075（其对BRD 4（1）的选择性是EP 300的63倍）相比，化合物38对BET溴结构域家族的选择性优于其他溴结构域，对BRD 4（1）的选择性类似于EP 300的1500倍。口服给药38实现了肿瘤生长的完全抑制，肿瘤生长抑制（TGI）为99.7%，并伴有良好的耐受性。
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 similar to 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.