Design, Synthesis,\nand Structural Evaluation of Acetylated\nPhenylthioketone Inhibitors of HDAC10

Histone deacetylase 10 (HDAC10) is unique among the greater\nHDAC\nfamily due to its unusually narrow substrate specificity as a polyamine\ndeacetylase, specifically as an <i>N</i><sup>8</sup>-acetylspermidine\nhydrolase. Polyamines are essential for cell growth and proliferation;\nconsequently, inhibition of polyamine deacetylation represents a possible\nstrategy for cancer chemotherapy. In this work, we have designed six\nacetylated phenylthioketone inhibitors of HDAC10 containing positively\ncharged <i>para</i>- and <i>meta</i>-substituted\namino groups designed to target interactions with E274, the gatekeeper\nthat recognizes the positively charged ammonium group of the substrate <i>N</i><sup>8</sup>-acetylspermidine. We prepared each of these\ninhibitors through a short synthetic route of six steps. By adapting\na low-cost colorimetric activity assay, we measured low-micromolar\nIC<sub>50</sub> values for these compounds against a humanized construct\nof zebrafish HDAC10 (A24E-D94A HDAC10). Selected inhibitors were cocrystallized\nwith A24E-D94A zebrafish HDAC10 and zebrafish HDAC6 to provide insight\ninto class IIb isozyme affinity and selectivity.