Identification of a small molecule SIRT2 inhibitor with selective tumor cytotoxicity.
As a member of the class III histone deacetylases, Sirtuin-2 (SIRT2) is critical in cell cycle regulation which makes it a potential target for cancer therapeutics. In this study, we identified a novel SIRT2 inhibitor, AC-93253, with IC(50) of 6 microM in vitro. The compound is selective, inhibiting SIRT2 7.5- and 4-fold more potently than the closely related SIRT1 and SIRT3, respectively. AC-93253 significantly enhanced acetylation of tubulin, p53, and histone H4, confirming SIRT2 and SIRT1 as its cellular targets. AC-93253 as a single agent exhibited submicromolar selective cytotoxicity towards all four tumor cell lines tested with a therapeutic window up to 200-fold, comparing to any of the three normal cell types tested. Results from high content analysis suggested that AC-93253 significantly triggered apoptosis. Taken together, SIRT2 selective inhibitor AC-93253 may serve as a novel chemical scaffold for structure-activity relationship study and future lead development.
Zhang
Yingjia
Y
Department of Biology, CytRx Corporation, 3030 Bunker Hill Street, Suite 101, San Diego, CA 92109, USA.
Au
Qingyan
Q
Zhang
Menghua
M
Barber
Jack R
JR
Ng
Shi Chung
SC
Zhang
Bin
B
D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors*
C542662:AC 93253; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D037761:Sirtuins