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

Inhibition of the bromodomain and
extra-terminal (BET) family of
adaptor proteins is an attractive strategy for targeting transcriptional
regulation of key oncogenes, such as c-MYC. Starting with the screening
hit 1, a combination of structure–activity relationship
and protein structure-guided drug design led to the discovery of a
differently oriented carbazole 9 with favorable binding
to the tryptophan, proline, and phenylalanine (WPF) shelf conserved
in the BET family. Identification of an additional lipophilic pocket
and functional group optimization to optimize pharmacokinetic (PK)
properties culminated in the discovery of 18 (BMS-986158)
with excellent potency in binding and functional assays. On the basis
of its favorable PK profile and robust in vivo activity in a panel
of hematologic and solid tumor models, BMS-986158 was selected as
a candidate for clinical evaluation.