Tag: Selective SIRT1 activator

SRT2104 (GSK2245840) is a synthetic, orally bioavailable, small-molecule allosteric activator of the NAD-dependent protein deacetylase sirtuin 1 (SIRT1, silent mating type information regulation 2 homolog 1), developed at Sirtris Pharmaceuticals and subsequently advanced into clinical trials by GlaxoSmithKline following the 2008 acquisition of Sirtris for approximately 720 million United States dollars. The compound is a second-generation sirtuin-activating compound (STAC) built on an optimized imidazo[2,1-b]thiazole scaffold and is reported to activate SIRT1 deacetylase activity approximately 1000-fold more potently than the natural polyphenol resveratrol in fluorophore-tagged peptide substrate assays, with minimal activity against a panel of more than 180 non-SIRT1 targets including kinases, G-protein-coupled receptors, nuclear receptors, ion channels, enzymes, and transporters [1, 2]. The allosteric mechanism involves binding to the N-terminal domain of SIRT1, lowering the Michaelis constant (Km) for the acetylated protein substrate without competing with either the NAD cofactor or the substrate acetyl-lysine site [3]. Downstream consequences of SIRT1 activation by SRT2104 include deacetylation and functional modulation of the transcription factor p53, the RelA/p65 subunit of nuclear factor kappa B (NF-kB), forkhead box protein O3 (FOXO3), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), and signal transducer and activator of transcription 3 (STAT3), producing composite anti-inflammatory, metabolic, and cytoprotective effects that have been characterized across a broad range of preclinical disease models [4, 5].

Pharmacokinetics in humans are characterized by oral absorption with time to peak plasma concentration of 1 to 3 hours after single dosing, a terminal elimination half-life of 8 to 24 hours depending on dose, and substantial inter-individual variability that is not dose-proportional across the studied range of 0.03 to 3.0 grams [6]. The variable and non-dose-proportional pharmacokinetic profile has been identified as a principal limitation of the compound for clinical development in its current oral formulation. SRT2104 is poorly soluble in water and is formulated as a lipid-based oral capsule to improve bioavailability.

Clinical evaluation has spanned at least seven registered clinical trials across multiple indications. In a Phase 1 trial in healthy elderly volunteers (60 to 80 years of age), 28 days of oral SRT2104 at 0.5 or 2.0 grams daily produced reductions in serum cholesterol, low-density lipoprotein, and triglycerides, with trends toward improved mitochondrial oxidative phosphorylation capacity as measured by phosphorus-31 magnetic resonance spectroscopy of skeletal muscle [7]. A Phase 2 randomized, placebo-controlled trial in 37 subjects with type 2 diabetes mellitus treated for 28 days at doses of 0.25, 0.5, 1.0, or 2.0 grams daily did not demonstrate improved glycemic control but produced a statistically significant reduction in total cholesterol and triglycerides at the 1.0 gram dose [8]. A separate cardiometabolic study in type 2 diabetic subjects reported trends toward improved endothelial function and arterial stiffness [9]. A Phase 2 trial in 40 subjects with moderate to severe psoriasis treated for 84 days at escalating doses of 250, 500, or 1000 milligrams daily reported 35 percent of SRT2104-treated patients achieving good to excellent histological improvement on skin biopsy, but three serious adverse events were reported including pneumonitis and pancreatitis [10]. A trial in mild to moderate ulcerative colitis (31 subjects, 50 or 500 milligrams daily for 8 weeks) demonstrated tolerability but limited clinical efficacy, with only 3 of 26 evaluable subjects achieving endoscopic remission [11]. In a human endotoxemia model, SRT2104 pretreatment significantly reduced lipopolysaccharide-induced cytokine release (interleukin-6, interleukin-8) and coagulation activation, representing the first human demonstration of anti-inflammatory and anticoagulant activity consistent with pharmacological SIRT1 activation [12].

Preclinical pharmacology is extensive. The Mercken et al. (2014) study at the National Institute on Aging demonstrated that SRT2104 extends both mean and maximum lifespan of male mice fed a standard diet by 9.7 percent and 4.9 percent respectively, with preserved bone mineral density, muscle mass, motor coordination, and insulin sensitivity [13]. The Jiang et al. (2014) study demonstrated blood-brain barrier penetration, attenuation of brain atrophy, improvement of motor function, and extension of median lifespan by approximately 16 percent in N171-82Q Huntington disease model mice [14]. Additional preclinical evidence spans emphysema, sepsis, neonatal white matter injury, microglia polarization, dendritic outgrowth, and auditory cell senescence. GlaxoSmithKline discontinued active clinical development of SRT2104 following the 2013 closure of the Sirtris unit, though the compound remains widely used as a reference SIRT1 activator in academic and preclinical research. This monograph reviews chemistry, molecular pharmacology, pharmacokinetics, the complete clinical evidence base, sourcing and handling, stack interactions, adverse events, and a comparative assessment of five SIRT1 modulators against SRT2104 on five competency standards.