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

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

  • J Med Chem. 2024 Jul 11;67(13):10743-10773. doi: 10.1021/acs.jmedchem.4c00242.
Hao Yin 1,  Menghan Zhang 2,  Congying Gu 1,  Zhenyu Li 3,  Chenyan Hao 1,  Junhui Wang 2 3,  Lulu Tian 3,  Kang Xu 1,  Xiangyu Hu 1,  Liqin Ming 1,  Min Zhang 3,  Zhanbo Wang 4,  Yong Yang 2 3,  Dayong Zhang 1,  Beiying Dai 2 3
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, Nanjing 211198, China.
  • 2 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
PMID: 38919032 DOI: 10.1021/acs.jmedchem.4c00242
Abstract

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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