Discovery of 8-Methyl-pyrrolo[1,2- a ]pyrazin-1(2 H )-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors

作者：Zizhou Li, Sen-Hao Xiao, Yaxi Yang, Chao Chen, Tian Lu, Zhifeng Chen, Hualiang Jiang, Shijie Chen, Cheng Luo, Bing Zhou · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.9b01784 · 被引用次数：31 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Ubiquitin and proteasome pathways

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(2 H )-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.