Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma,Journal of Medicinal Chemistry

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Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-07-27 , DOI: 10.1021/acs.jmedchem.3c01008
Zhencheng Lai ₁ , Hao Ni _{1,

2} , Xueping Hu ₃ , Sunliang Cui _{1,

2}

Affiliation

The development of histone deacetylase (HDAC) inhibitors for treating hematologic malignancies has been widely investigated, while their role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we employed a scaffold-hopping design and a multicomponent synthesis approach to develop a novel series of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridines as HDAC inhibitors. There were a total of 29 compounds achieved with flexible linkers and zinc-binding groups, wherein compound 12k was identified as a promising candidate with good HDAC inhibitory activity, pharmacokinetic profiles, and potency. It exhibited significant therapeutic efficacy in HCC cell lines (IC₅₀ = 30 nM for Bel-7402) and xenograft models (76% inhibition for Bel-7402 xenografts, P.O. at 20 mg/kg, QOD, for 14 days) and was found to upregulate the acetylation of histone H3 and α-tubulin, leading to apoptosis and autophagy in HCC models. Molecular docking studies indicated a unique T-shaped conformation of 12k with the catalytic domain of HDAC1. Therefore, this work provides a new structure design for HDAC inhibitors and also offers a promising treatment for HCC.

中文翻译：

发现新型 1,2,3,4-四氢苯并呋喃[2,3-c]吡啶组蛋白脱乙酰酶抑制剂可有效治疗肝细胞癌

用于治疗血液恶性肿瘤的组蛋白脱乙酰酶 (HDAC) 抑制剂的开发已得到广泛研究，但其在肝细胞癌 (HCC) 中的作用仍有待探索。在这项研究中，我们采用支架跳跃设计和多组分合成方法开发了一系列新型 1,2,3,4-四氢苯并呋喃[2,3- c ]吡啶作为 HDAC 抑制剂。总共获得了 29 种具有柔性接头和锌结合基团的化合物，其中化合物12k被确定为具有良好 HDAC 抑制活性、药代动力学特征和效力的有前途的候选化合物。它在 HCC 细胞系（Bel-7402 的 IC ₅₀ = 30 nM）和异种移植模型（Bel-7402 异种移植物的抑制率为 76%，PO 20 mg/kg，QOD，持续 14 天）中表现出显着的治疗功效，并被发现上调组蛋白 H3 和 α-微管蛋白的乙酰化，导致 HCC 模型中的细胞凋亡和自噬。分子对接研究表明12k与 HDAC1 催化结构域具有独特的 T 形构象。因此，这项工作为HDAC抑制剂提供了一种新的结构设计，也为HCC的治疗提供了一种有前景的方法。

更新日期：2023-07-27

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