Discovery of a potent, orally available tricyclic derivative as a novel BRD4 inhibitor for melanoma

The epigenetic regulation of the protein bromodomain-containing protein 4 (BRD4) has emerged as a compelling target for Cancer treatment. In this study, we outline the discovery of a novel BRD4 Inhibitor for melanoma therapy. Our initial finding was that benzimidazole derivative 1, sourced from our library, was a powerful BRD4 Inhibitor. However, it exhibited a poor pharmacokinetic (PK) profile. To address this, we conducted a scaffold-hopping procedure with derivative 1, which resulted in the creation of benzimidazolinone derivative 5. This new derivative displayed an improved PK profile. To further enhance the BRD4 inhibitory activity, we attempted to introduce hydrogen bond acceptors. This indeed improved the activity, but at the cost of decreased membrane permeability. Our search for a potent inhibitor with desirable permeability led to the development of tricyclic 18. This compound demonstrated powerful inhibitory activity and a favorable PK profile. More significantly, tricyclic 18 showed antitumor efficacy in a mouse melanoma xenograft model, suggesting that it holds potential as a therapeutic agent for melanoma treatment.

BRD4 inhibitors; Hydrogen bond acceptor; Melanoma; Permeability; Pharmacokinetics; Scaffold-hopping; Structure-activity relationship.