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 <b>SelSA</b> as a novel HDAC6 inhibitor (HDAC6i) for HCC therapy. In this work, we optimized this inhibitor and discovered <b>14a</b> 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 <b>14a</b> markedly induced apoptosis and cell cycle arrest at the S phase in HepG2 cells. Mechanistic studies demonstrated that <b>14a</b> effectively downregulated the levels of HDAC6 and the phosphorylation of ERK1/2, and attenuated the migration, invasion, and clonogenicity of HepG2 cells. More crucially, <b>14a</b> possessed more potency to suppress tumor growth in HepG2 xenograft models compared to SelSA, without obvious toxicity. In summary, <b>14a</b> represents a novel HDAC6i with anti-HCC effects.