SIRT1/2 Inhibitor IV

SIRT1/2 Inhibitor IV (cambinol) is a small-molecule inhibitor of SIRT1 and SIRT2 with IC50 values of 56 ?M and 59 ?M, respectively [1].

Sirtuin 1 (SIRT1) and SIRT2 are NAD-dependent deacetylases and are members of sirtuin family protein. SIRT1 regulate pathways in metabolism, inflammation and tumorigenesis and SIRT2 functions as a tubulin deacetylase[2].

SIRT1/2 Inhibitor IV is a cell-permeable SIRT1 and SIRT2 inhibitor. SIRT1/2 Inhibitor IV inhibited human SIRT1 and SIRT2 NAD-dependent deacetylase activity with IC50 values of 56 and 59 ?mol/L, respectively. In NCI H460 lung cancer cell line, combined inhibition of SIRT2 and HDAC6 with SIRT1/2 Inhibitor IV and trichostatin A resulted in hyperacetylation of tubulin. SIRT1/2 Inhibitor IV also increased acetylation of p53. In p53-positive lung cancer cell line NCI H460, SIRT1/2 Inhibitor IV mediated inhibition of SIRT1 sensitized cells to etoposide in p53-independent manner [1].

In a mouse xenograft model, SIRT1/2 Inhibitor IV (100 mg/kg) administered i.v. into the tail vein or i.p. daily for 2 weeks (five injections per week) reduced tumor growth [1]. In mice pre-treated with cambinol for 2 hours and then exposed to 6% oxygen for 6 hours, cambinol significantly reduced EPO mRNA in the kidney and the liver [2].

References:
Heltweg B, Gatbonton T, Schuler AD, et al.  Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 2006 Apr 15;66(8):4368-77.
Laemmle A, Lechleiter A, Roh V, et al.  Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1α protein under hypoxic conditions. PLoS One. 2012;7(3):e33433.