Discovery of Novel 2-Oxoacetamide Derivatives as B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Beta-1,3-glucuronosyltransferase (B3GAT3), overexpressed in hepatocellular carcinoma (HCC) and negatively correlated to prognosis, is a promising target for cancer therapy. Currently, no studies have reported small molecule inhibitors of B3GAT3. In this study, we designed and synthesized a series of small-molecule inhibitors of B3GAT3 through virtual screening and structure optimization. The lead compound TMLB-C16 exhibited potent B3GAT3 inhibitory activity (KD = 3.962 μM) by effectively suppressing proliferation and migration, and inducing cell cycle arrest and apoptosis in MHCC-97H (IC ₅₀ = 6.53 ± 0.18 μM) and HCCLM3 (IC ₅₀ = 6.22 ± 0.23 μM) cells. Furthermore, compound TMLB-C16 demonstrated favorable pharmacokinetic properties with a relatively high bioavailability of 68.37%. It significantly inhibited tumor growth in both MHCC-97H and HCCLM3 xenograft tumor models without causing obvious toxicity. These results indicate that compound TMLB-C16 is an effective small molecule inhibitor of B3GAT3, providing a basis for the future development of B3GAT3-targeted drugs.