The dysregulation of histone acetylation contributes to the pathogenesis of some cancers. Histone deacetylases (HDACs), which participate in regulating the acetylation status of nucleosomal histones, are increasingly recognized as promising targets for cancer therapy. (S)-HDAC-42 is a potent inhibitor of HDACs (IC50 = 16 nM in vitro). It decreases the viability of prostate cancer cell lines (IC50 = 0.40 μM), increasing the expression of p21 and the acetylation of histone H3 while decreasing the phosphorylation of Akt and the expression of Bcl-XL. (S)-HDAC-42 also strongly suppresses the growth of PC-3 tumor xenografts, reducing levels of phospho-Akt and Bcl-XL protein in tumors.