Target Validation Information
Target ID T14731
Target Name NAD-dependent deacetylase sirtuin-1
Target Type
Clinical Trial
Drug Potency against Target BISINDOLYLMALEIMIDE IX Drug Info IC50 = 5100 nM [528556]
2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide Drug Info IC50 = 3300 nM [527917]
Para-sirtinol Drug Info IC50 = 13000 nM [527886]
2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione Drug Info IC50 = 5300 nM [530608]
Action against Disease Model SRT501 Resveratrol (100-150 microM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. [553053] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Sirtuin1 (Sirt1), a mammalian homolog of yeast Sir2, deacetylates the t uMor suppressor protein p53 and attenuates p53-mediated cell death. Necdin, a p53-interacting protein expressed predominantly in postmitotic neurons, is a melanoma antigen family protein that promotes neuronal differentiation and survival. In mammals, the necdin gene (Ndn) is maternally imprinted, and mutant mice carrying mutated paternal Ndn show abnormalities of neuronal development. Here we report that necdin regulates the acetylation status of p53 via Sirt1 to suppress p53-dependent apoptosis in postmitotic neurons. Double-immunostaining analysis demonstrated that necdin colocalizes with Sirt1 in postmitotic neurons of mouse embryonic forebrain in vivo. Coimmunoprecipitation and in vitro binding analyses revealed that necdin interacts with both p53 and Sirt1 to potentiate Sirt1-mediated p53 deacetylation by facilitating their association. Primary cortical neurons prepared from paternal Ndn-deficient mice have high p53 acetylation levels and are sensitive to the DNA-damaging compounds camptothecin and hydrogen peroxide. Moreover, DNA transfection per se increases p53 acetylation and apoptosis in paternal Ndn-deficient neurons, whereas small interfering RNA-mediated p53 knockdown completely blocks these changes. However, Sirt1 knockdown increases both acetylated p53 level and apoptosis in wild-type neurons but fails to affect them in paternal Ndn-deficient neurons. In organotypic forebrain slice cultures treated with hydrogen peroxide, p53 is acc uMulated and colocalized with necdin and Sirt1 in cortical neurons. These results suggest that necdin downregulates p53 acetylation levels by forming a stable complex with p53 and Sirt1 to protect neurons from DNA damage-induced apoptosis [553053]
References
Ref 553053Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer. 2010 May 26;10:238. doi: 10.1186/1471-2407-10-238.
Ref 528556J Med Chem. 2006 Dec 14;49(25):7307-16.Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.
Ref 527917J Med Chem. 2005 Dec 15;48(25):8045-54.Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1.
Ref 527886J Med Chem. 2005 Dec 1;48(24):7789-95.Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors.
Ref 530608J Med Chem. 2010 Feb 11;53(3):1407-11.Characterization of sirtuin inhibitors in nematodes expressing a muscular dystrophy protein reveals muscle cell and behavioral protection by specific sirtinol analogues.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.