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

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-]pyrazin-1(2)-one fragment () as a new binder to the BET bromodomains and the subsequent incorporation of fragment to the scaffold of , 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 as a potential preclinical candidate. Significantly, compared with , which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.