Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design

Inhibiting the bromodomain and extra-terminal (BET) family of adaptor proteins offers a promising approach for targeting the transcriptional regulation of crucial oncogenes like c-MYC. Beginning with an initial screening hit, compound 1, we employed a combination of structure-activity relationship studies and protein structure-guided drug design to identify a carbazole derivative, compound 9, with a new orientation that binds effectively to the tryptophan, proline, and phenylalanine (WPF) shelf conserved across the BET family.

Further optimization included identifying an additional lipophilic pocket and refining functional groups to enhance pharmacokinetic (PK) properties. This process led to the development of compound 18 (BMS-986158), which demonstrated excellent potency in binding and functional assays. Due to its favorable PK profile and significant in vivo activity across various hematologic and solid tumor models, BMS-986158 was chosen for clinical evaluation.