Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.
Journal of medicinal and pharmaceutical chemistry 56(9):3666 (2013)
The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA enc...
Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man.
British Journal of Clinical Pharmacology 75(1):186 (2013)
SRT2104 is a novel, first-in-class, highly selective small molecule activator of the NAD + dependent deacetylase SIRT1. SRT2104 was dosed to healthy male and female volunteers in a series of phase 1 clinical studies that were designed to elucidate tolerability and pharmacokinetics associated wit...
Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators.
Bioorganic & Medicinal Chemistry Letters 19(8):2350 (2009)
SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival i...
Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators.
Journal of medicinal and pharmaceutical chemistry 52(5):1275 (2009)
A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-so...
Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.
BMC Systems Biology 3:31 (2009)
Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetyl...
Sirtuins--novel therapeutic targets to treat age-associated diseases.
Nature Reviews: Drug Discovery 7(10):841 (2008)
Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation-deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in pr...
Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity?
Experimental Gerontology 41(8):718 (2006)
Eukaryotes have evolved elaborate mechanisms to survive periods of adversity. By manipulating genes that control these mechanisms, researchers have found they can generate more stress resistant, longer-lived organisms. One of these is the PNC1 gene of Saccharomyces cerevisiae, a master "longevit...
Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors.
Journal of Medicinal Chemistry 48(24):7789 (2005)
In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Tw...
Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
Nature 430(7000):686 (2004)
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the r...
Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis.
Molecular Cell 13(5):627 (2004)
Apoptosis is a key tumor suppression mechanism that can be initiated by activation of the proapoptotic factor Bax. The Ku70 DNA end-joining protein has recently been shown to suppress apoptosis by sequestering Bax from mitochondria. The mechanism by which Bax is regulated remains unknown. Here, ...
Acetylation of the C Terminus of Ku70 by CBP and PCAF Controls Bax-Mediated Apoptosis
Molecular Cell 13(5):627 (2004)
Apoptosis is a key tumor suppression mechanism that can be initiated by activation of the proapoptotic factor Bax. The Ku70 DNA end-joining protein has recently been shown to suppress apoptosis by sequestering Bax from mitochondria. The mechanism by which Bax is regulated remains unknown. H...
Yeast life-span extension by calorie restriction is independent of NAD fluctuation.
Science 302(5653):2124 (2003)
Calorie restriction (CR) slows aging in numerous species. In the yeast Saccharomyces cerevisiae, this effect requires Sir2, a conserved NAD+-dependent deacetylase. We report that CR reduces nuclear NAD+ levels in vivo. Moreover, the activity of Sir2 and its human homologue SIRT1 are not affected...
Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
Nature 425(6954):191 (2003)
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein...