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

The development of histone deacetylase (HDAC) inhibitorsfor treatinghematologic malignancies has been widely investigated, while theirrole in hepatocellular carcinoma (HCC) remains unexplored. In thisstudy, we employed a scaffold-hopping design and a multicomponentsynthesis approach to develop a novel series of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridines as HDAC inhibitors. There were a total of 29compounds achieved with flexible linkers and zinc-binding groups,wherein compound 12k was identified as a promising candidatewith good HDAC inhibitory activity, pharmacokinetic profiles, andpotency. It exhibited significant therapeutic efficacy in HCC celllines (IC50 = 30 nM for Bel-7402) and xenograft models(76% inhibition for Bel-7402 xenografts, P.O. at 20 mg/kg, QOD, for14 days) and was found to upregulate the acetylation of histone H3and & alpha;-tubulin, leading to apoptosis and autophagy in HCC models.Molecular docking studies indicated a unique T-shaped conformationof 12k with the catalytic domain of HDAC1. Therefore,this work provides a new structure design for HDAC inhibitors andalso offers a promising treatment for HCC.