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

Hao YinMenghan ZhangCongying GuZhenyu LiChenyan HaoJunhui WangLulu TianKang XuXiangyu HuLiqin MingMin ZhangZhanbo WangYong YangDayong ZhangBeiying Dai
Published in: Journal of medicinal chemistry (2024)
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.
Keyphrases
  • small molecule
  • cell cycle arrest
  • cell death
  • cancer therapy
  • pi k akt
  • protein protein
  • oxidative stress
  • signaling pathway
  • induced apoptosis
  • cell proliferation
  • high throughput
  • single cell