Discovery of Novel 2-Oxoacetamide Derivatives as B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma,Journal of Medicinal Chemistry

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Discovery of Novel 2-Oxoacetamide Derivatives as B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-06-25 , 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}

Affiliation

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.

中文翻译：

发现新型 2-氧代乙酰胺衍生物作为 B3GAT3 抑制剂用于治疗肝细胞癌

Beta-1,3-葡萄糖醛酸基转移酶 (B3GAT3) 在肝细胞癌 (HCC) 中过度表达且与预后呈负相关，是癌症治疗的一个有前景的靶点。目前，尚无研究报道B3GAT3的小分子抑制剂。本研究通过虚拟筛选和结构优化，设计合成了一系列B3GAT3小分子抑制剂。先导化合物TMLB-C16通过有效抑制增殖和迁移并诱导 MHCC-97H (IC ₅₀ = 6.53 ± 0.18 μM) 和 HCCLM3 (IC ₅₀ = 6.22 ± 0.23 μM) 细胞。此外，化合物TMLB-C16表现出良好的药代动力学特性，具有相对较高的生物利用度（68.37%）。它在 MHCC-97H 和 HCCLM3 异种移植肿瘤模型中均显着抑制肿瘤生长，且不引起明显毒性。这些结果表明化合物TMLB-C16是一种有效的B3GAT3小分子抑制剂，为未来开发B3GAT3靶向药物奠定了基础。

更新日期：2024-06-25

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