化学
肝细胞癌
药理学
组合化学
癌症研究
医学
生物
作者
Hao Yin,Menghan Zhang,Congying Gu,Zhenyu Li,Chenyan Hao,J. Wang,Lulu Tian,Kang Xu,Xiangyu Hu,Liqin Ming,Min Zhang,Zhanbo Wang,Yong Yang,Dayong Zhang,Beiying Dai
标识
DOI:10.1021/acs.jmedchem.4c00242
摘要
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 (IC50= 6.53 ± 0.18 μM) and HCCLM3 (IC50= 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.
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