Discovery of an orally bioavailable pyridone-based BRD4 inhibitor with potent antitumor efficacy in colorectal cancer.

Colorectal cancer (CRC) remains a major clinical burden with limited durable responses. Given reports implicating Bromodomain-containing protein 4 (BRD4) in CRC proliferation and therapy resistance, more potent BRD4-targeting agents with proven in-vivo activity are needed. Through virtual screening followed by structure-guided chemical modification, we identified H5 as a BRD4 inhibitor. In biochemical assays, H5 shows IC50 = 7.9 ± 0.5 nM, outperforming JQ-1 (IC50 = 33.0 ± 1.0 nM) by 4-fold. Molecular dynamics simulations indicate that H5 engages BRD4 via hydrogen bonds with Asn140 and Asp88 and a water-mediated bridge to Gln85. In the HCT-116 xenograft mouse model, oral administration of H5 suppressed tumor growth (TGI = 82 % at 50 mg/kg) and downregulated the BRD4-driven oncoproteins c-MYC and BCL-2. Collectively, H5 emerges as a highly promising BRD4-targeted candidate for colorectal cancer treatment.