Discovering a potent and orally available imidazopyridine derivative as a BRD4 inhibitor: Enhancing antiproliferative activity against melanoma cells by mitigating P-gp substrate recognition.

Bromodomain-containing protein 4 (BRD4), a crucial epigenetic regulator in cancer, has become a critical target for melanoma therapy. Herein, we investigated a strategy for enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. A compound that exhibits antitumor effects in a mouse melanoma xenograft model at doses lower than those required for previously reported compound 1 is required. Therefore, we focused on enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. Our hypothesis state that mitigating P-glycoprotein (P-gp) substrate recognition can improve cell permeability and enhance cellular inhibitory activity. Thus, we reduced the hydrogen-bond donors (HBDs) of a benzimidazole core through N-alkylation. Using this approach, we successfully enhanced the cellular inhibitory activity by mitigating P-gp substrate recognition; however, the compounds derived from this approach exhibited poor metabolic stability. To overcome this issue, we used a scaffold-hopping strategy to identify core-lacking HBDs and discovered the imidazopyridine derivative 17. This compound exhibits potent antiproliferative activity against melanoma cells and good oral exposure. Thus, we conclude that mitigation of P-gp substrate recognition can effectively enhance cellular activity and identify favorable antitumor agents.