GSK 2245840 / GSK - LARVOL DELTA

Synthesis of Primary Thioamides by the Insertion of CS2 into Aldoximes. (PubMed, Org Lett) - "Its robustness has been demonstrated on the synthesis of active drug Febuxostat (gout) and an advanced intermediate in the synthesis of SRT2104 (type 2 diabetes). Computational studies, based on DFT calculations, have revealed the roles of both the base and TBACl in the reaction and have elucidated the reaction mechanism, which differs significantly from those displayed for other CS2 insertions."

Journal • Diabetes • Gout • Inflammatory Arthritis • Metabolic Disorders • Rheumatology • Type 2 Diabetes Mellitus

SIRT1 mediates brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism. (PubMed, Cell Rep Med) - "SRT2104 treatment restores mitochondrial and energy metabolism, normalizes Wnt signaling and neurogenesis markers, and rescues learning and memory performance. These findings identify SIRT1 as a therapeutic target in B12-related neurodevelopmental disorders and support the clinical repurposing of SRT2104 to alleviate persistent neurological symptoms."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Metabolic Disorders • Psychiatry • Solid Tumor • SIRT1

SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells. (PubMed, Sci Rep) - "Our findings demonstrated that SRT2104 alleviates premature senescence and promotes mitophagy in auditory cells via SIRT1 activation. The pharmacological activation of SIRT1 may represent a promising therapeutic strategy to counteract age-related degeneration in the auditory system."

Journal • CNS Disorders • Metabolic Disorders • Otorhinolaryngology • CDKN1A

Targeting autophagy in Duchenne muscular dystrophy: mechanistic insights and emerging therapeutic strategies. (PubMed, J Med Genet) - "Recent preclinical studies highlight the therapeutic potential of pharmacological and dietary autophagy modulators, including rapamycin, 5-aminoimidazole-4-carboxamide ribonucleotide, low protein diets, SRT2104 and Givinostat, which improve autophagic flux, restore mitochondrial integrity and attenuate fibrosis. Lifestyle interventions and combinatorial approaches further underscore the importance of integrating multimodal strategies.Further research should focus on longitudinal studies to optimise therapeutic timing, validate dynamic biomarkers (LC-II, p62, miRNAs) and leverage artificial intelligence with multiomics integration for precision therapies. Targeting autophagy and its interconnected pathways holds promise for transforming DMD management and improving patient outcomes."

Journal • Review • CNS Disorders • Duchenne Muscular Dystrophy • Fibrosis • Gene Therapies • Genetic Disorders • Immunology • Metabolic Disorders • Muscular Atrophy • Muscular Dystrophy • Musculoskeletal Diseases • Myositis • Respiratory Diseases

Sirtuin downregulation mediates mitochondrial impairment causing cognitive decline in hepatic encephalopathy. (PubMed, Free Radic Biol Med) - "Pharmacological activation of Sirtuin 1 with SRT2104 suppressed HIF-1α levels and reduced VDAC1 expression, while inhibition with EX-527 exerted the opposite effect and worsened mitochondrial dysfunction. Loss of Sirtuin 6 further amplified HIF-1α transcriptional activity by reducing its interaction with Sirtuin 6 and diminishing Sirtuin 6-mediated repression, thereby promoting increased expression of the downstream target VDAC1. Together, these observations identify reduced nuclear Sirtuin 1 and Sirtuin 6 as converging upstream regulators of the HIF-1α-VDAC1 axis, contributing to mitochondrial dysfunction in HE."

Journal • CNS Disorders • Hepatic Encephalopathy • Metabolic Disorders • HIF1A • VDAC1

The Sirt1-Piezo1 Axis Promotes Bone Formation and Repair in Mice. (PubMed, Adv Sci (Weinh)) - "Piezo1 loss in chondrocytes abolishes the ability of Sirt1 activator SRT2104 to accelerate bone repair...A yeast microcapsule-based oral formulation of RSV (YC-RSV) is developed to improve drug bioavailability and therapeutic efficacy, which highly and selectively targets to the inflammatory fracture site. Thus, it demonstrates that Sirt1 is a novel and potent activator of Piezo1 to promote bone formation and repair, supporting the potential clinical application of Sirt1 activators in promoting bone formation and repair."

Journal • Preclinical • Musculoskeletal Diseases • Orthopedics

The SIRT1 activator SRT2104 mitigates hypoxia-induced white matter injury in neonatal mice. (PubMed, Brain Res) - "Behavioral improvements were observed in locomotor activity, motor coordination, and cognitive function in treated mice. In summary, SRT2104 demonstrates protective effects against hypoxia-induced WMI by promoting oligodendrocyte survival and myelination, suggesting its potential as a therapeutic agent for WMI in neonatal hypoxia."

Journal • Preclinical • CNS Disorders • Solid Tumor • Vascular Neurology • CASP3 • MBP • SIRT1

Vitamin D and SIRT1 activator SRT2104 cooperate in antiproliferative activity in lung cancer through ferroptosis induction. (PubMed, Biomed Pharmacother) - "This effect may be due to the induction of ferroptosis. These insights pave the way for potential to use SIRT1 activators with vitamin D derivatives in the treatment of lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • CDC37 • CYP24A1 • EGFR • HSP90AA1 • PTGS2 • VDR

SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling. (PubMed, Sci Rep) - "Conversely, sirtuin 1 knockdown by siRNA transfection markedly reduced ERK1/2 and mTORC1 phosphorylation, as well as dendritic complexity and spine formation. These results suggest that sirtuin 1 promotes neuroplasticity by activating mTORC1 signaling, providing potential therapeutic implications for depression treatment."

Journal • CNS Disorders • Depression • Psychiatry • EIF4EBP1 • SIRT1

Upregulation of SIRT1 ameliorates apoptosis of rat nucleus pulposus cells under oxidative stress through FoxO1/β-catenin pathway. (PubMed, Folia Histochem Cytobiol) - "These results suggest that activation of the SIRT1/FoxO1/β-Catenin axis can diminish ageing-related phenotypes and cell apoptosis in NPCs, inhibiting the oxidative stress-induced ageing process triggered by H₂O₂. These findings may offer a new perspective for the treatment of intervertebral disc degeneration (IDD) in the future."

Journal • Preclinical • Back Pain • Musculoskeletal Pain • Pain • FOXO1

Pseudomonas Aeruginosa Toxin ExoY Inhibits SIRT-1 Mediated Autophagy to Promote Pulmonogenic Tauopathy (ATS 2025) - "These data suggest that ExoY suppresses autophagy via SIRT1 to promote cytotoxic tau generation and release. Furthermore, repurposing the clinical SIRT1 agonist SRT2104 at bedside may represent a feasible therapeutic for preventing the long-term poor outcomes associated with recovery from nosocomial pneumonia."

Infectious Disease • Pneumonia • Respiratory Diseases • SIRT1

The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery. (PubMed, Cell Death Dis) - "Further, the impact of SRT2104 in reshaping muscle proteome and acetylome profiles has been investigated, highlighting effects that mimic those induced by exercise. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract DMD progression."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Metabolic Disorders • Muscular Dystrophy • SIRT1

Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer. (PubMed, Oncogene) - "Combined treatment with low doses of the SIRT1-specific activator SRT2104 and the LDHA inhibitor oxamate exerted significant antitumor effects on GC cells, with limited adverse effects on normal gastric cells...Therefore, SIRT1 acts as a histone delactylase for H3K18, and loss of SIRT1 triggers a positive feedback loop involving H19/glycolysis/H3K18la. Targeting this pathway serves as a novel therapeutic strategy for GC treatment."

Journal • Gastric Cancer • Oncology • Solid Tumor • H19 • LDHA • SIRT1

Acetylation of FOXO1 is involved in cadmium-induced rat kidney injury via mediating autophagosome-lysosome fusion blockade and autophagy inhibition. (PubMed, Ecotoxicol Environ Saf) - "Pharmacological activation of Sirt1 (SRT2104 treatment) decreases Cd-increased acetylation level of FOXO1, enhances Cd-inhibited transcription level of Ras-related protein 7 (Rab7), restores Cd-blocked fusion of autophagosome and lysosome, and alleviates Cd-induced autophagy inhibition. Moreover, data corroborated that inhibiting the acetylation level of FOXO1 is conductive to mitigating Cd-induced kidney injury. Collectively, these results demonstrate that acetylation of FOXO1 mediates the autophagosome-lysosome fusion blockade and autophagy inhibition during Cd-induced kidney injury, while regulating the acetylation level of FOXO1 may be a potential mechanism of treating nephrotoxicity after Cd exposure."

Journal • Preclinical • Renal Disease • SIRT1

The Role of Sirtuin 1 in Ageing and Neurodegenerative Disease: A Molecular Perspective. (PubMed, Ageing Res Rev) - "Preclinical studies have demonstrated that SIRT1 activators, such as resveratrol, SRT1720, and SRT2104, can alleviate disease symptoms by reducing oxidative stress, enhancing autophagic flux, and promoting neuronal survival. Ongoing clinical trials are evaluating the efficacy of these SIRT1 activators, providing hope for future therapeutic strategies targeting SIRT1 in neurodegenerative diseases. This review explores the role of SIRT1 in ageing and neurodegenerative diseases, with a particular focus on its molecular mechanisms, therapeutic potential, and clinical applications."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • SIRT1

Bone-targeting engineered milk-derived extracellular vesicles for MRI-assisted therapy of osteoporosis. (PubMed, Regen Biomater) - "The obtained nanocomposites significantly prevented bone loss in osteoporosis mice and increased bone mineral density, exhibiting superior bone accumulation under MRI. We believe the proposed (DSS)6-mEV-SRT2104/MnB provides a novel paradigm for osteoporosis treatment and monitoring."

Journal • Osteoporosis • Rheumatology • SIRT1

Small molecule SIRT1 activators counteract oxidative stress-induced inflammasome activation and nucleolar stress in retinal degeneration. (PubMed, Int Immunopharmacol) - "Our study suggests that small molecule SIRT1 activators are effective for protection of RPE cells against oxidative stress-induced NLRP3 inflammasome activation, highlighting potential applications in the treatment of macular degeneration associated RPE dysfunctions."

Journal • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • IL18 • IL1B • NLRP3

Unveiling the Regulatory Role of SIRT1 in Oxidative Stress Response of bovine mammary cells. (PubMed, J Dairy Sci) - "Further investigation showed that SIRT1 inhibitor (EX 527) could reverse the enhanced cellular antioxidant capacity triggered by short-term oxidative stress...Conversely, the SIRT1 activator (SRT 2104) could reverse the reduced cellular antioxidant capacity caused by long-term oxidative stress and significantly inhibit the accumulation of ROS and MDA...In summary, SIRT1 plays a crucial role in regulating the antioxidant capacity of mammary epithelial cells in dairy cows. This discovery provides valuable insights into the antioxidant mechanisms of mammary cells, which can serve as a theoretical foundation for future mammary health strategies."

Journal • AMPK • NQO1 • SIRT1 • SOD2

Sirt1 inhibits macrophage polarization and inflammation in gouty arthritis by inhibiting the MAPK/NF-κB/AP-1 pathway and activating the Nrf2/HO-1 pathway. (PubMed, Inflamm Res) - "Sirt1 alleviates M1 macrophage polarization and inflammation in gouty arthritis by inhibiting the MAPK/NF-κB/AP-1 pathway and activating the Nrf2/HO-1 pathway. Thus, activating Sirt1 may provide a new therapeutic target for gouty arthritis."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatology • CD68

Emerging roles of SIRT1 activator, SRT2104, in disease treatment. (PubMed, Sci Rep) - "The findings reveal that SRT2104, as a potent SIRT1 activator, holds considerable therapeutic potential, particularly in modulating metabolic and longevity-related pathways. This review establishes SRT2104 as a leading SIRT1 activator with significant therapeutic promise."

Journal

Arc regulates brain damage and neuroinflammation via Sirt1 signaling following subarachnoid hemorrhage. (PubMed, Brain Res Bull) - "In addition, activation of sirtuin 1 (Sirt1) via agonist SRT2104 markedly decreased the brain damage and neuroinflammation induced by Arc knockdown. In conclusion, knockdown of endogenous Arc could aggravate brain damage and neuroinflammation following experimental SAH, and Arc levels in aSAH patients' CSF might be a potential indicator of brain damage and prognosis."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • SIRT1

The Impact of SRT2104 on Skeletal Muscle Mitochondrial Function, Redox Biology, and Loss of Muscle Mass in Hindlimb Unloaded Rats. (PubMed, Int J Mol Sci) - "In the soleus, HO concentration was greater in HU compared to CON. These results indicate that SRT2104 preserves mitochondrial function in unloaded skeletal muscle, suggesting its potential to support healthy muscle cells in microgravity by promoting necessary energy production in mitochondria."

Journal • Preclinical • Metabolic Disorders • Muscular Atrophy

Neuroprotection of SRT2104 in Murine Ischemia/Reperfusion Injury Through the Enhancement of Sirt1-Mediated Deacetylation. (PubMed, Invest Ophthalmol Vis Sci) - "Mechanistically, I/R-induced acetylation of p53, NF-κB p65, and STAT3 was significantly reversed by SRT2104 intervention. We demonstrated that SRT2104 exerted potent protective effects against I/R injury by enhancing Sirt1-mediated deacetylation and suppressing apoptosis, senescence, and neuroinflammation-related pathways."

Journal • Preclinical • Cardiovascular • Glaucoma • Inflammation • Ophthalmology • Reperfusion Injury • NF-κβ • SIRT1 • STAT3

Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2. (PubMed, Front Pharmacol) - "Activation of autophagy by rapamycin also resulted in reduction of PKM2. In addition, co-administration of 3-methyladenine, an autophagy inhibitor, or Bafilomycin A1, a lysosome inhibitor, abolished the suppressive effects of SRT2104 on PKM2 abundance, inflammatory response and multiple organ injury. Therefore, promotion of autophagic degradation of PKM2 might be a novel mechanism underlying the anti-inflammatory benefits of SIRT1 activator."

Journal • Inflammation • Respiratory Diseases • PKM • SIRT1

Cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation and pulmonary hypertension. (PubMed, Sci Signal) - "In two rodent models of PH, SRT2104 treatment restored TSC2 abundance, attenuated pulmonary vascular remodeling, and ameliorated PH. Thus, TSC2 in PAVSMCs integrates ECM composition and stiffness with pro-proliferative and survival signaling, and restoring TSC2 abundance could be an attractive therapeutic option to treat PH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • FN1 • TSC2