A Small Molecule SIRT2 Inhibitor that Promotes K-Ras4a Lysine Fatty-acylation.

SIRT2, a member of the sirtuin family of protein lysine deacylases, has been identified as a promising therapeutic target. In addition to catalyzing deacetylation, SIRT2 has recently been shown to remove fatty acyl groups from K-Ras4a and promote its transforming activity. Among the SIRT2 specific inhibitors, only the thiomyristoyl lysine compound, TM, can weakly inhibit the demyristoylation activity of SIRT2. Thus, more potent small molecule SIRT2 inhibitors are needed to further evaluate the therapeutic potential of SIRT2 inhibition, and to understand the function of protein lysine defatty-acylation. Here we report a SIRT2 inhibitor, JH-T4, which can increase intracellular K-Ras4a lysine fatty acylation. This is the first small molecule inhibitor that can modulate the lysine fatty acylation levels of K-Ras4a. JH-T4 also inhibits SIRT1 and SIRT3 in vitro. The increased potency of JH-T4 is likely due to the formation of hydrogen bonding between the hydroxyl group of JH-T4 and SIRT1, SIRT2, and SIRT3. This is further supported by in vitro studies with another small molecule inhibitor, NH-TM. These studies provide useful insights for future SIRT2 inhibitor development.