Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status


Previously, we designed and synthesized a series of <i>o</i>-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound <b>11a</b> exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using <b>11a</b> as a lead. Representative compound <b>13b</b> showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound <b>13e</b> exhibited low nanomolar IC<sub>50</sub>s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC<sub>50</sub> of <b>13e</b> against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound <b>11a</b>. <i>In vitro</i> responses to <b>13e</b> vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, <b>13e</b> induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, <b>13e</b> caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis

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