Identification of 3-arylquinoxalin-2(1H)-one derivatives targeting BRD4 BD1 as efficient anticancer agents

BRD4 is a key epigenetic reader protein critically involved in the growth and proliferation of both hematological malignancies and solid tumors. Developing selective BRD4 BD1 inhibitors with novel scaffolds has emerged as a promising strategy to address the limitations of current agents. Through a scaffold fusion approach, a series of 3-arylquinoxalin-2(1H)-one derivatives with promising BRD4 BD1 inhibitory activity were designed and synthesized. The optimized compound B12 demonstrated excellent BRD4 BD1 inhibitory activity (IC₅₀ = 0.82 μM) and high selectivity over BRD4 BD2 (22-fold). B12 could effectively suppress the migration and proliferation of A549 cells (IC₅₀ = 0.73 μM). Mechanistic studies revealed that B12 treatment could effectively downregulate c-Myc and anti-apoptotic protein expression, increase DNA damage, elevate ROS levels, reduce mitochondrial membrane potential, and trigger Apoptosis. Molecular docking suggested that B12 selectively binds to the active site of BRD4 BD1 through key hydrogen bonds with Asn140 and Asp144. Moreover, B12 showed favorable pharmacokinetic properties. Taken together, our research highlights that the 3-arylquinoxalin-2(1H)-one scaffold could serve as a valuable backbone for BRD4 inhibition and B12 is a promising candidate for further investigation.