Target Information

Target General Infomation
Target ID
T14731
Former ID
TTDC00052
Target Name
NAD-dependent deacetylase sirtuin-1
Gene Name
SIRT1
Synonyms
SIR2-like protein 1; SIR2L1; hSIR2; hSIRT1; SIRT1
Target Type
Clinical Trial
Disease Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Colon cancer; Hematologic cancers; Type 2 diabetes [ICD9: 140-229, 250, 250.00, 250.02; ICD10: E08-E13, E11]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Huntington's disease [ICD9: 294.1, 333.4; ICD10: F02.2, G10]
Obesity [ICD9: 278; ICD10: E66]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Function
SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly.
BioChemical Class
Carbon-nitrogen hydrolase
Target Validation
T14731
UniProt ID
Q96EB6
EC Number
EC 3.5.1.-
Sequence
MADEAALALQPGGSPSAAGADREAASSPAGEPLRKRPRRDGPGLERSPGEPGGAAPEREV
PAAARGCPGAAAAALWREAEAEAAAAGGEQEAQATAAAGEGDNGPGLQGPSREPPLADNL
YDEDDDDEGEEEEEAAAAAIGYRDNLLFGDEIITNGFHSCESDEEDRASHASSSDWTPRP
RIGPYTFVQQHLMIGTDPRTILKDLLPETIPPPELDDMTLWQIVINILSEPPKRKKRKDI
NTIEDAVKLLQECKKIIVLTGAGVSVSCGIPDFRSRDGIYARLAVDFPDLPDPQAMFDIE
YFRKDPRPFFKFAKEIYPGQFQPSLCHKFIALSDKEGKLLRNYTQNIDTLEQVAGIQRII
QCHGSFATASCLICKYKVDCEAVRGDIFNQVVPRCPRCPADEPLAIMKPEIVFFGENLPE
QFHRAMKYDKDEVDLLIVIGSSLKVRPVALIPSSIPHEVPQILINREPLPHLHFDVELLG
DCDVIINELCHRLGGEYAKLCCNPVKLSEITEKPPRTQKELAYLSELPPTPLHVSEDSSS
PERTSPPDSSVIVTLLDQAAKSNDDLDVSESKGCMEEKPQEVQTSRNVESIAEQMENPDL
KNVGSSTGEKNERTSVAGTVRKCWPNRVAKEQISRRLDGNQYLFLPPNRYIFHGAEVYSD
SEDDVLSSSSCGSNSDSGTCQSPSLEEPMEDESEIEEFYNGLEDEPDVPERAGGAGFGTD
GDDQEAINEAISVKQEVTDMNYPSNKS
Drugs and Mode of Action
Drug(s) GSK2245840 Drug Info Phase 2 Chronic obstructive pulmonary disease [523097]
MB-12066 Drug Info Phase 2 Obesity [524589]
SEN-196 Drug Info Phase 2 Huntington's disease [523783], [542972]
SRT2379 Drug Info Phase 1 Type 2 diabetes [522863]
SRT3025 Drug Info Phase 1 Type 2 diabetes [523447]
GSK184072 Drug Info Discontinued in Phase 2 Colon cancer; Hematologic cancers; Type 2 diabetes [548320]
Inhibitor (R)-sirtinol Drug Info [527886]
(S)-sirtinol Drug Info [527886]
2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide Drug Info [527917]
2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione Drug Info [530608]
BISINDOLYLMALEIMIDE IX Drug Info [528556]
CAMBINOL Drug Info [530103]
Meta-sirtinol Drug Info [527886]
Para-sirtinol Drug Info [527886]
RO-316233 Drug Info [528556]
SEN-196 Drug Info [531699]
splitomicin Drug Info [530608]
YK-3237 Drug Info [543687]
Activator GSK184072 Drug Info [550963]
SRT1720 Drug Info [529184]
Modulator GSK2245840 Drug Info [533004], [533102]
MB-12066 Drug Info
SRT2379 Drug Info [550534]
SRT3025 Drug Info [533296]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway FoxO signaling pathway
AMPK signaling pathway
Glucagon signaling pathway
Amphetamine addiction
MicroRNAs in cancer
PANTHER Pathway p53 pathway
Pathway Interaction Database p73 transcription factor network
Signaling events mediated by HDAC Class III
E2F transcription factor network
HIF-2-alpha transcription factor network
Signaling events mediated by HDAC Class I
FoxO family signaling
Regulation of Androgen receptor activity
Regulation of retinoblastoma protein
Reactome RORA activates gene expression
Regulation of HSF1-mediated heat shock response
Circadian Clock
WikiPathways Integrated Pancreatic Cancer Pathway
SREBF and miR33 in cholesterol and lipid homeostasis
Integrated Breast Cancer Pathway
SREBP signalling
Androgen receptor signaling pathway
References
Ref 522863ClinicalTrials.gov (NCT01018628) A Clinical Study to Assess the Safety and Pharmacokinetics of SRT2379 in Normal Healthy Male Volunteers. U.S. National Institutes of Health.
Ref 523097ClinicalTrials.gov (NCT01154101) Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects With Moderate to Severe Plaque-Type Psoriasis. U.S. National Institutes of Health.
Ref 523447ClinicalTrials.gov (NCT01340911) A Study in Healthy Male Volunteers to Investigate Different Doses of a New Drug for the Treatment of Metabolic Diseases. U.S. National Institutes of Health.
Ref 523783ClinicalTrials.gov (NCT01521585) A Phase II Safety and Tolerability Study With SEN0014196. U.S. National Institutes of Health.
Ref 524589ClinicalTrials.gov (NCT02029586) Therapeutic Exploratory Phase 2 Study to Evaluate the Safety and Efficacy of MB12066 in Patients With Nonalcoholic Fatty Liver Disease(NAFLD) Except Cirrhosis. U.S. National Institutes of Health.
Ref 542972(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8100).
Ref 548320Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024569)
Ref 527886J Med Chem. 2005 Dec 1;48(24):7789-95.Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors.
Ref 527917J Med Chem. 2005 Dec 15;48(25):8045-54.Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1.
Ref 528556J Med Chem. 2006 Dec 14;49(25):7307-16.Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.
Ref 529184Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6.
Ref 530103J Med Chem. 2009 May 14;52(9):2673-82.Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity.
Ref 530608J Med Chem. 2010 Feb 11;53(3):1407-11.Characterization of sirtuin inhibitors in nematodes expressing a muscular dystrophy protein reveals muscle cell and behavioral protection by specific sirtinol analogues.
Ref 531699Sirtuin 1 (SIRT1): the misunderstood HDAC. J Biomol Screen. 2011 Dec;16(10):1153-69.
Ref 533004Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs. 2015 Mar;24(3):283-307.
Ref 533102Sirtuin 1 activator SRT2104 protects Huntington's disease mice. Ann Clin Transl Neurol. 2014 Dec;1(12):1047-52.
Ref 533296The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells. PLoS One. 2015 Jul 30;10(7):e0134391.
Ref 543687(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2707).
Ref 550534SRT2379, a small-molecule SIRT1 activator, fails to reduce cytokine release in a human endotoxemia model. Critical Care 2013, 17(Suppl 4):P8.
Ref 550963Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).

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