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Article ; Online: Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation.

Kato, Taro / Pothula, Santosh / Liu, Rong-Jian / Duman, Catharine H / Terwilliger, Rosemarie / Vlasuk, George P / Saiah, Eddine / Hahm, Seung / Duman, Ronald S

The Journal of clinical investigation

2019 Volume 129, Issue 6, Page(s) 2542–2554

Abstract: Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which ... ...

Abstract	Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.
MeSH term(s)	Animals ; Antidepressive Agents/chemistry ; Antidepressive Agents/pharmacokinetics ; Antidepressive Agents/pharmacology ; Behavior, Animal/drug effects ; Brain-Derived Neurotrophic Factor/genetics ; Brain-Derived Neurotrophic Factor/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Male ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Mice, Knockout ; Rats ; Rats, Sprague-Dawley ; Synaptic Transmission/drug effects ; Synaptic Transmission/genetics
Chemical Substances	Antidepressive Agents ; Bdnf protein, mouse ; Bdnf protein, rat ; Brain-Derived Neurotrophic Factor ; Heat-Shock Proteins ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2019-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI126859
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Article ; Online: Discovery of NV-5138, the first selective Brain mTORC1 activator.

Sengupta, Shomit / Giaime, Emilie / Narayan, Sridhar / Hahm, Seung / Howell, Jessica / O'Neill, David / Vlasuk, George P / Saiah, Eddine

Scientific reports

2019 Volume 9, Issue 1, Page(s) 4107

Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 ... ...

Abstract	The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.
MeSH term(s)	Administration, Oral ; Animals ; Brain/metabolism ; Drug Design ; Drug Discovery ; HEK293 Cells ; Humans ; Leucine/administration & dosage ; Leucine/analogs & derivatives ; Leucine/pharmacokinetics ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Neurons/metabolism ; Nuclear Proteins/metabolism ; Protein Binding ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Recombinant Proteins/metabolism ; Transaminases/metabolism
Chemical Substances	NV-5138 ; Nuclear Proteins ; RNA, Messenger ; Recombinant Proteins ; SESN2 protein, human ; Transaminases (EC 2.6.1.-) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Leucine (GMW67QNF9C)
Language	English
Publishing date	2019-03-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-40693-5
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Article ; Online: Inhibitors of Factor VIIa/tissue factor.

Shirk, Rebecca A / Vlasuk, George P

Arteriosclerosis, thrombosis, and vascular biology

2007 Volume 27, Issue 9, Page(s) 1895–1900

Abstract: The formation of the proteolytic complex composed of the serine protease Factor VIIa and the cell-associated glycoprotein tissue factor (FVIIa/TF) initiates a cascade of amplified zymogen activation reactions leading to thrombus formation. The critical ... ...

Abstract	The formation of the proteolytic complex composed of the serine protease Factor VIIa and the cell-associated glycoprotein tissue factor (FVIIa/TF) initiates a cascade of amplified zymogen activation reactions leading to thrombus formation. The critical role of the coagulation cascade in pathological thrombosis has been the basis for significant efforts to design selective inhibitors of the protease components as new anticoagulant alternatives for the treatment of thrombotic diseases. However, for the new generation of anticoagulant drugs in development that primarily target protease complexes distal from FVIIa/TF, the differential between efficacy and safety as defined by bleeding is unresolved. Targeting the FVIIa/TF complex has several theoretical advantages that exploit the amplified nature of the coagulation cascade. However, progress on the development of clinical-stage FVIIa/TF-based anticoagulants has not been as successful to date. This review summarizes recent efforts in the discovery of synthetic inhibitors of FVIIa/TF.
MeSH term(s)	Anticoagulants/chemistry ; Anticoagulants/pharmacology ; Drug Design ; Factor VIIa/antagonists & inhibitors ; Humans ; Serine Proteinase Inhibitors/chemistry ; Serine Proteinase Inhibitors/pharmacology ; Thromboplastin/antagonists & inhibitors
Chemical Substances	Anticoagulants ; Serine Proteinase Inhibitors ; Thromboplastin (9035-58-9) ; Factor VIIa (EC 3.4.21.21)
Language	English
Publishing date	2007-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.107.148304
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Article ; Online: A small molecule inhibitor of Rheb selectively targets mTORC1 signaling.

Mahoney, Sarah J / Narayan, Sridhar / Molz, Lisa / Berstler, Lauren A / Kang, Seong A / Vlasuk, George P / Saiah, Eddine

Nature communications

2018 Volume 9, Issue 1, Page(s) 548

Abstract: The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, ... ...

Abstract	The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential.
MeSH term(s)	Animals ; Cell Line, Tumor ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Jurkat Cells ; MCF-7 Cells ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice, Inbred C57BL ; Molecular Structure ; Phosphorylation/drug effects ; Ras Homolog Enriched in Brain Protein/antagonists & inhibitors ; Ras Homolog Enriched in Brain Protein/genetics ; Ras Homolog Enriched in Brain Protein/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	RHEB protein, human ; Ras Homolog Enriched in Brain Protein ; Small Molecule Libraries ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1) ; ribosomal protein S6 kinase, 70kD, polypeptide 1 (EC 2.7.11.1)
Language	English
Publishing date	2018-02-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-018-03035-z
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Article ; Online: Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters.

Kang, Seong A / O'Neill, David J / Machl, Andreas W / Lumpkin, Casey J / Galda, Stephanie N / Sengupta, Shomit / Mahoney, Sarah J / Howell, Jessica J / Molz, Lisa / Hahm, Seung / Vlasuk, George P / Saiah, Eddine

Cell chemical biology

2019 Volume 26, Issue 9, Page(s) 1203–1213.e13

Abstract: The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic ... ...

Abstract	The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic treatment in certain cell types and in vivo results in the inhibition of both mTORC1 and mTORC2. We have developed a high-throughput cell-based screen for the detection of phosphorylated forms of the mTORC1 (4E-BP1, S6K1) and mTORC2 (Akt) substrates and have identified and characterized a chemical scaffold that demonstrates a profile consistent with the selective inhibition of mTORC1. Stable isotope labeling of amino acids in cell culture-based proteomic target identification revealed that class I glucose transporters were the primary target for these compounds yielding potent inhibition of glucose uptake and, as a result, selective inhibition of mTORC1. The link between the glucose uptake and selective mTORC1 inhibition are discussed in the context of a yet-to-be discovered glucose sensor.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Evaluation, Preclinical/methods ; Glucose/metabolism ; Glucose Transport Proteins, Facilitative/drug effects ; High-Throughput Screening Assays/methods ; Humans ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mechanistic Target of Rapamycin Complex 2/drug effects ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/metabolism ; Phosphorylation ; Proteomics/methods ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Sirolimus/analogs & derivatives ; Sirolimus/metabolism ; Sirolimus/pharmacology ; Transcription Factors/metabolism
Chemical Substances	Glucose Transport Proteins, Facilitative ; Multiprotein Complexes ; Transcription Factors ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Glucose (IY9XDZ35W2) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2019-06-20
Publishing country	United States
Document type	Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2019.05.009
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Article: Inhibition of factor VIIa/tissue factor with nematode anticoagulant protein c2: from unique mechanism to a promising new clinical anticoagulant.

Vlasuk, George P / Rote, William E

Trends in cardiovascular medicine

2003 Volume 12, Issue 8, Page(s) 325–331

Abstract: Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent (K(i) = 10 pM) inhibitor of the factor VIIa/tissue factor complex (fVIIa/TF) that involves the pre-requisite binding to either zymogen or activated factor X (fX) prior to the formation of ...

Abstract	Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent (K(i) = 10 pM) inhibitor of the factor VIIa/tissue factor complex (fVIIa/TF) that involves the pre-requisite binding to either zymogen or activated factor X (fX) prior to the formation of the final quaternary complex with fVIIa/TF. The formation of the binary complex with circulating fX governs the pharmacokinetic profile of rNAPc2 in humans, resulting in a prolonged elimination half-life of >50 h. The clinical antithrombotic potential of rNAPc2 has been evaluated in a phase-II trial in which the incidence of deep-vein thrombosis was reduced over 50% compared to historic controls with low-molecular-weight heparin in patients undergoing knee replacement surgery. A second phase-IIa trial demonstrated the safety of rNAPc2 and the significant suppression of thrombin generation in patients undergoing elective percutaneous coronary intervention treated with standard anticoagulant and antiplatelet therapies. Overall, rNAPc2 is a unique inhibitor of the fVIIa/TF complex and a promising new clinical anticoagulant.
MeSH term(s)	Anticoagulants/pharmacology ; Factor VIIa/antagonists & inhibitors ; Factor VIIa/drug effects ; Helminth Proteins/pharmacology ; Hemostatics/antagonists & inhibitors ; Humans ; Thromboplastin/antagonists & inhibitors ; Thromboplastin/drug effects
Chemical Substances	Anticoagulants ; Helminth Proteins ; Hemostatics ; anti-coagulant protein C2, Ancylostoma caninum ; Thromboplastin (9035-58-9) ; Factor VIIa (EC 3.4.21.21)
Language	English
Publishing date	2003-01-17
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1097434-9
ISSN	1873-2615 ; 1050-1738
ISSN (online)	1873-2615
ISSN	1050-1738
DOI	10.1016/s1050-1738(02)00185-8
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Zs.A 3419: Show issues

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Article ; Online: A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.

Baksi, Arun / Kraydashenko, Oleg / Zalevkaya, Alsu / Stets, Roman / Elliott, Peter / Haddad, Jonathan / Hoffmann, Ethan / Vlasuk, George P / Jacobson, Eric W

British journal of clinical pharmacology

2014 Volume 78, Issue 1, Page(s) 69–77

Abstract: Aim: SRT2104 is a selective activator of SIRT1. In animal models, SRT2104 improves glucose homeostasis and increases insulin sensitivity. We evaluated the tolerability and pharmacokinetics of SRT2104, and its effects on glycaemic control, in adults with ...

Abstract	Aim: SRT2104 is a selective activator of SIRT1. In animal models, SRT2104 improves glucose homeostasis and increases insulin sensitivity. We evaluated the tolerability and pharmacokinetics of SRT2104, and its effects on glycaemic control, in adults with type 2 diabetes mellitus. Method: Type 2 diabetics with glycosylated haemoglobin (HbA1c) ≥ 7.5% and ≤10.5%, fasting glucose ≥160 and ≤240 mg dl(-1) , and on stable doses of metformin were evenly randomized to placebo or SRT2104 0.25 g, 0.5 g, 1.0 g or 2.0 g, administered orally once daily for 28 days. Changes in fasting and post-prandial glucose and insulin were analyzed. Results: Safety evaluation found no major differences between groups in the frequency of adverse events. SRT2104 concentrations did not increase in a dose-proportional fashion. Significant variability in exposure was observed. Treatment with SRT2104 did not lead to any consistent, dose-related changes in glucose or insulin. Day 28 change from baseline (mean (SD)): fasting glucose (mmol l(-1) ) = -1.17 (2.42), -1.11 (3.45), -0.52 (2.60), -0.97 (2.83) and -0.15 (2.38) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively. Day 28 change from baseline (mean (SD)): fasting insulin (mmol l(-1) ) = 1.0 (51.66), 8.9 (95.04), -6.9 (41.45), 4.1 (57.16) and 15.2 (138.79) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively) Treatment with SRT2104 was associated with improvement in lipid profiles. Conclusion: Treatment with SRT2104 for 28 days did not result in improved glucose or insulin control which is likely due to the observed pharmacokinetics which were not dose proportional and had large between subject variability.
MeSH term(s)	Adult ; Aged ; Blood Glucose/drug effects ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/drug therapy ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Therapy, Combination ; Enzyme Activation/drug effects ; Enzyme Activators/adverse effects ; Enzyme Activators/pharmacokinetics ; Enzyme Activators/pharmacology ; Enzyme Activators/therapeutic use ; Female ; Heterocyclic Compounds, 2-Ring/adverse effects ; Heterocyclic Compounds, 2-Ring/pharmacokinetics ; Heterocyclic Compounds, 2-Ring/pharmacology ; Heterocyclic Compounds, 2-Ring/therapeutic use ; Humans ; Insulin/blood ; Male ; Metformin/therapeutic use ; Middle Aged ; Sirtuin 1/metabolism
Chemical Substances	Blood Glucose ; Enzyme Activators ; Heterocyclic Compounds, 2-Ring ; Insulin ; SRT2104 ; Metformin (9100L32L2N) ; SIRT1 protein, human (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2014-01-20
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.12327
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Article ; Online: PHARMACOLOGICAL SIRT1 ACTIVATION IMPROVES MORTALITY AND MARKEDLY ALTERS TRANSCRIPTIONAL PROFILES THAT ACCOMPANY EXPERIMENTAL SEPSIS.

Opal, Steven M / Ellis, James L / Suri, Vipin / Freudenberg, Johannes M / Vlasuk, George P / Li, Yong / Chahin, Abdullah B / Palardy, John E / Parejo, Nicholas / Yamamoto, Michelle / Chahin, Abdulrahman / Kessimian, Noubar

Shock (Augusta, Ga.)

2016 Volume 45, Issue 4, Page(s) 411–418

Abstract: The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by ...

Abstract	The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025's effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection.
MeSH term(s)	Anilides/pharmacology ; Animals ; Disease Models, Animal ; Enzyme Activation/drug effects ; Enzyme Activation/immunology ; Female ; Immunity, Innate/drug effects ; Mice ; Sepsis/drug therapy ; Sepsis/immunology ; Sepsis/pathology ; Sirtuin 1/immunology ; Streptococcal Infections/drug therapy ; Streptococcal Infections/immunology ; Streptococcal Infections/pathology ; Streptococcus pneumoniae ; Thiazoles/pharmacology ; Transcription, Genetic/drug effects ; Transcription, Genetic/immunology
Chemical Substances	Anilides ; SRT3025 ; Thiazoles ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2016-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1185432-7
ISSN	1540-0514 ; 1073-2322
ISSN (online)	1540-0514
ISSN	1073-2322
DOI	10.1097/SHK.0000000000000528
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Zs.A 3985: Show issues

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Article: Structural and Functional Characterization of Tick Anticoagulant Peptide (TAP): A Potent and Selective Inhibitor of Blood Coagulation Factor Xa

Vlasuk, George P

Thrombosis and Haemostasis

1993 Volume 70, Issue 01, Page(s) 212–216

Language	English
Publishing date	1993-01-01
Publisher	Schattauer GmbH
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0038-1646193
Database	Thieme publisher's database

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Uh III Zs.192: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis.

Krueger, James G / Suárez-Fariñas, Mayte / Cueto, Inna / Khacherian, Artemis / Matheson, Robert / Parish, Lawrence C / Leonardi, Craig / Shortino, Denise / Gupta, Akanksha / Haddad, Jonathan / Vlasuk, George P / Jacobson, Eric W

PloS one

2015 Volume 10, Issue 11, Page(s) e0142081

Abstract: Unlabelled: Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three ...

Abstract	Unlabelled: Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo. Across all SRT2104 groups, 35% of patients (p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84 but was not consistently in agreement with PASI. Improvement in histology was associated with modulation of IL-17 and TNF-α signaling pathways and keratinocyte differentiation target genes. 27 subjects (69%) across all treatment groups, including placebo, experienced at least one treatment emergent adverse event. The majority of AEs were either mild or moderate. Most common were headache (8%), dizziness (8%), upper respiratory tract infection (8%), and psoriatic arthropathy (8%). Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104 and had high intra-subject variability in exposure (AUC %CV: 51–89%). Given the interesting signals of clinical activity, impact on gene expression and the generally favorable safety profile seen in this study, further investigation of SIRT1 activators for the treatment of psoriasis is warranted. Trial registration: Clinicaltrials.gov NCT01154101.
MeSH term(s)	Adult ; Aged ; Double-Blind Method ; Enzyme Activators/therapeutic use ; Female ; Heterocyclic Compounds, 2-Ring/therapeutic use ; Humans ; Male ; Middle Aged ; Psoriasis/drug therapy ; Psoriasis/metabolism ; Sirtuin 1/metabolism ; Treatment Outcome ; Young Adult
Chemical Substances	Enzyme Activators ; Heterocyclic Compounds, 2-Ring ; SRT2104 ; SIRT1 protein, human (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2015
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0142081
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