Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
Sirtris Pharmaceuticals Inc., 790 Memorial Drive, Cambridge, Massachusetts 02139, USA.
Jill C
JC
Milne
Philip D
PD
Lambert
Simon
S
Schenk
David P
DP
Carney
Jesse J
JJ
Smith
David J
DJ
Gagne
Lei
L
Jin
Olivier
O
Boss
Robert B
RB
Perni
Chi B
CB
Vu
Jean E
JE
Bemis
Roger
R
Xie
Jeremy S
JS
Disch
Pui Yee
PY
Ng
Joseph J
JJ
Nunes
Amy V
AV
Lynch
Hongying
H
Yang
Heidi
H
Galonek
Kristine
K
Israelian
Wendy
W
Choy
Andre
A
Iffland
Siva
S
Lavu
Oliver
O
Medvedik
David A
DA
Sinclair
Jerrold M
JM
Olefsky
Michael R
MR
Jirousek
Peter J
PJ
Elliott
Christoph H
CH
Westphal
D000107:Acetylation; D000495:Allosteric Site; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D031204:Caloric Restriction; D020134:Catalytic Domain; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000819:agonists* / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology
D001786:Blood Glucose; D004041:Dietary Fats; D006576:Heterocyclic Compounds, 4 or More Rings; D007328:Insulin; C525424:SRT1460; C525422:SRT1720; C525423:SRT2183; D013267:Stilbenes; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol