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

• Published in: Journal of medicinal chemistry Vol. 66; no. 15; pp. 10791 - 10807
• Main Authors: Lai, Zhencheng, Ni, Hao, Hu, Xueping, Cui, Sunliang
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.08.2023; Amer Chemical Soc
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Benzofurans - chemistry; Benzofurans - pharmacology; Benzofurans - therapeutic use; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation; Chemistry, Medicinal; Histone Deacetylase 1 - metabolism; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Life Sciences & Biomedicine; Liver Neoplasms - pathology; Molecular Docking Simulation; Pharmacology & Pharmacy; Pyridines - chemistry; Pyridines - pharmacology; Pyridines - therapeutic use; Science & Technology; HDAC INHIBITORS; DESIGN; POTENT; EFFICACY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01008

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.