Discovery of Novel Selenocyanate Derivatives as Histone Deacetylase 6 Inhibitors for the Treatment of Hepatocellular Carcinoma

Histone deacetylase 6 (HDAC6) is a pivotal epigenetic regulator and is involved in the tumorigenesis and progression. Our previous study revealed that HDAC6 is overactivated in hepatocellular carcinoma (HCC), and identified SelSA as a novel HDAC6 inhibitor (HDAC6i) for HCC therapy. In this work, we optimized this inhibitor and discovered 14a as a novel HDAC6i with better efficacy against HDAC6 and HepG2 cells than SelSA through structure–activity relationship (SAR) studies. The flow cytometry indicated that 14a markedly induced apoptosis and cell cycle arrest at the S phase in HepG2 cells. Mechanistic studies demonstrated that 14a effectively downregulated the levels of HDAC6 and the phosphorylation of ERK1/2, and attenuated the migration, invasion, and clonogenicity of HepG2 cells. More crucially, 14a possessed more potency to suppress tumor growth in HepG2 xenograft models compared to SelSA, without obvious toxicity. In summary, 14a represents a novel HDAC6i with anti-HCC effects.