生物活性

• 靶点	Sirtuin 1 IC50:38nM

• 描述SIRT1 is an enzyme which can remove acetyl groups without hydrolysis of NAD⁺ and can deacetylate p53 to modulate its function such as DNA damage-induced cell death. EX-527 is a novel, potent, and specific inhibitor of SIRT1 catalytic activity with IC50 value of 38nM (measure by activity of GST-tagged human SIRT1 purified from 293T cells), almost no activity to SIRT2 (IC50=19.6μM) or SIRT3 (IC50=48.7μM). Treatment with 1μM EX-527 for 6h after DNA damage by etoposide could enhance the level of p53 acetylation on K382 site in NCI-H460 cells. And this inhibition of SIRT1 catalytic activity by EX-527 could also be observed after treatment with adriamycin, hydroxyurea, or hydrogen peroxide in NCI-H460 cells, or in U-2 OS, MCF-7 and HMEC treated with etoposide. However, p53-controlled gene expression, such as p21, as well as cell survival or proliferation are not altered by inhibition of SIRT1 through EX-527 in these p53-positive cell lines. Inhibition of Sirt by EX-527 induced apoptosis-like changes in blood platelets, associated with a rise in active Bax and a significant drop in platelet count. Administration of 20mg/kg EX-527 led to a reduction in the number of reticulated platelets and thrombocytopenia in mice.

• 动物研究
  剂量	Mice: 10 mg/kg[3] (i.p.); 5 mg/kg - 100 mg/kg[4] (p.o.); 20 mg/kg25829495 (i.v.)
  给药途径	i.p., p.o., i.v.
  动物药代数据	Animal Mice[4] Dose 20 mg/kg Administration p.o. Css 3.2 ± 0.4 µM T1/2 0.9 ± 0.2 h AUC0→last 77.5 ± 9.7 µM·h Tmax 0.50 ± 0.0 h Cmax 29.3 ± 6.4 µM