Tenovin-D3, a Novel Small-Molecule Inhibitor of Sirtuin SirT2, Increases p21 (CDKN1A) Expression in a p53-Independent Manner

Whilst small molecule inhibitors of class I/II histone deacetylases (HDACs) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies demonstrate that tenovin-6, a small molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here we describe a tenovin analog, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell cycle regulator and p53 target p21WAF1/CIP1 ( CDKN1A ) in a p53-independent manner. Structure-activity relationship studies strongly support that tenovin-D3's ability to inhibit SirT2 contributes to this p53-independent induction of p21. Tenovin-D3's ability to increase p21 mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell cycle progression.