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

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-06-25 DOI:10.1021/acs.jmedchem.4c00242

Hao Yin, Menghan Zhang, Congying Gu, Zhenyu Li, Chenyan Hao, Junhui Wang, Lulu Tian, Kang Xu, Xiangyu Hu, Liqin Ming, Min Zhang, Zhanbo Wang, Yong Yang*, Dayong Zhang* and Beiying Dai*,

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引用次数: 0

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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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。

β-1,3-葡萄糖醛酸基转移酶（B3GAT3）在肝细胞癌（HCC）中过度表达，并与预后呈负相关，是一种很有前景的癌症治疗靶点。目前，还没有关于 B3GAT3 小分子抑制剂的研究报道。在本研究中，我们通过虚拟筛选和结构优化设计并合成了一系列 B3GAT3 小分子抑制剂。先导化合物 TMLB-C16 在 MHCC-97H 细胞（IC50= 6.53 ± 0.18 μM）和 HCCLM3 细胞（IC50= 6.22 ± 0.23 μM）中有效抑制细胞增殖和迁移，诱导细胞周期停滞和凋亡，从而表现出强效的 B3GAT3 抑制活性（KD = 3.962 μM）。此外，化合物 TMLB-C16 表现出良好的药代动力学特性，生物利用度相对较高，为 68.37%。它在 MHCC-97H 和 HCCLM3 异种移植肿瘤模型中都能明显抑制肿瘤生长，且无明显毒性。这些结果表明，化合物TMLB-C16是一种有效的B3GAT3小分子抑制剂，为今后开发B3GAT3靶向药物奠定了基础。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.