Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUF2HO)

• DTT Name: NAD-dependent deacetylase sirtuin-1 (SIRT1)
• Synonyms: hSIRT1; hSIR2; SIR2L1; SIR2-like protein 1; Regulatory protein SIR2 homolog 1; NAD-dependent protein deacetylase sirtuin-1
• Gene Name: SIRT1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Carbon-nitrogen hydrolase
• UniProt ID: SIR1_HUMAN
• TTD ID: T14731
• EC Number: EC 3.5.1.-
• Sequence:
  MADEAALALQPGGSPSAAGADREAASSPAGEPLRKRPRRDGPGLERSPGEPGGAAPEREV
  PAAARGCPGAAAAALWREAEAEAAAAGGEQEAQATAAAGEGDNGPGLQGPSREPPLADNL
  YDEDDDDEGEEEEEAAAAAIGYRDNLLFGDEIITNGFHSCESDEEDRASHASSSDWTPRP
  RIGPYTFVQQHLMIGTDPRTILKDLLPETIPPPELDDMTLWQIVINILSEPPKRKKRKDI
  NTIEDAVKLLQECKKIIVLTGAGVSVSCGIPDFRSRDGIYARLAVDFPDLPDPQAMFDIE
  YFRKDPRPFFKFAKEIYPGQFQPSLCHKFIALSDKEGKLLRNYTQNIDTLEQVAGIQRII
  QCHGSFATASCLICKYKVDCEAVRGDIFNQVVPRCPRCPADEPLAIMKPEIVFFGENLPE
  QFHRAMKYDKDEVDLLIVIGSSLKVRPVALIPSSIPHEVPQILINREPLPHLHFDVELLG
  DCDVIINELCHRLGGEYAKLCCNPVKLSEITEKPPRTQKELAYLSELPPTPLHVSEDSSS
  PERTSPPDSSVIVTLLDQAAKSNDDLDVSESKGCMEEKPQEVQTSRNVESIAEQMENPDL
  KNVGSSTGEKNERTSVAGTVRKCWPNRVAKEQISRRLDGNQYLFLPPNRYIFHGAEVYSD
  SEDDVLSSSSCGSNSDSGTCQSPSLEEPMEDESEIEEFYNGLEDEPDVPERAGGAGFGTD
  GDDQEAINEAISVKQEVTDMNYPSNKS
• Function: Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A-mediated transcription. Required for the repression of ESRRG by CREBZF. Deacetylates NR1H3 and NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates p300/EP300 and PRMT1. Deacetylates ACSS2 leading to its activation, and HMGCS1 deacetylation. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1-dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transactivation and contributes to its stability. Deacteylates MECOM/EVI1. Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization. During the neurogenic transition, repress selective NOTCH1-target genes through histone deacetylation in a BCL6-dependent manner and leading to neuronal differentiation. Regulates the circadian expression of several core clock genes, including ARNTL/BMAL1, RORC, PER2 and CRY1 and plays a critical role in maintaining a controlled rhythmicity in histone acetylation, thereby contributing to circadian chromatin remodeling. Deacetylates ARNTL/BMAL1 and histones at the circadian gene promoters in order to facilitate repression by inhibitory components of the circadian oscillator. Deacetylates PER2, facilitating its ubiquitination and degradation by the proteosome. Protects cardiomyocytes against palmitate-induced apoptosis. Deacetylates XBP1 isoform 2; deacetylation decreases protein stability of XBP1 isoform 2 and inhibits its transcriptional activity. Deacetylates PCK1 and directs its activity toward phosphoenolpyruvate production promoting gluconeogenesis. Involved in the CCAR2-mediated regulation of PCK1 and NR1D1. Deacetylates CTNB1 at 'Lys-49'. In POMC (pro-opiomelanocortin) neurons, required for leptin-induced activation of PI3K signaling. NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  AMPK signaling pathway (hsa04152)
  Glucagon signaling pathway (hsa04922)
  Amphetamine addiction (hsa05031)
  MicroRNAs in cancer (hsa05206)
• Reactome Pathway:
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  Circadian Clock (R-HSA-400253)
  RORA activates gene expression (R-HSA-1368082)
• BioCyc Pathway: MetaCyc:ENSG00000096717-MON

Molecular Interaction Atlas (MIA) of This DTT

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Resveratrol	DM3RWXL	Giant cell arteritis	4A44.2	Phase 3	[2]
GSK2245840	DMG7YQL	Chronic obstructive pulmonary disease	CA22	Phase 2	[3]
MB-12066	DMRSN2C	Obesity	5B81	Phase 2	[4]
SEN-196	DMLDBQ5	Huntington disease	8A01.10	Phase 2	[1]
SRT2379	DM7DAKX	Type-2 diabetes	5A11	Phase 1	[5]
SRT3025	DMRAXFH	Type-2 diabetes	5A11	Phase 1	[6]

4 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CAMBINOL	DMW46GY	Discovery agent	N.A.	Patented	[7]
PMID25435179-Compound-WO2012106509CAY10602	DM2F1T0	N. A.	N. A.	Patented	[2]
PMID25435179-Compound-WO2012106509Salermide	DMLAH39	N. A.	N. A.	Patented	[2]
PMID25435179-Compound-WO2012106509Tenovin-6	DMBSOED	N. A.	N. A.	Patented	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK184072	DMMIR1K	Colon cancer	2B90.Z	Discontinued in Phase 2	[8]

11 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(R)-sirtinol	DMV1IS8	Discovery agent	N.A.	Investigative	[9]
(S)-sirtinol	DMS8WG3	Discovery agent	N.A.	Investigative	[9]
2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide	DMXAS25	Discovery agent	N.A.	Investigative	[10]
2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione	DMET6FO	Discovery agent	N.A.	Investigative	[11]
Meta-sirtinol	DMSK0QX	Discovery agent	N.A.	Investigative	[9]
Para-sirtinol	DM83C9N	Discovery agent	N.A.	Investigative	[9]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[12]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[12]
splitomicin	DMCLHZ5	Discovery agent	N.A.	Investigative	[11]
SRT1720	DMUKVHQ	Discovery agent	N.A.	Investigative	[13]
YK-3237	DMU0NHX	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	7.82E-01	-0.16	-0.27
Rectal cancer	2C82	Rectal colon tissue	2.00E-01	-0.14	-0.38
Chronic obstructive pulmonary disease	CA23	Lung tissue	7.25E-01	-0.06	-0.16
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	2.92E-05	-0.25	-0.64

References

• [1] Sirtuin 1 (SIRT1): the misunderstood HDAC. J Biomol Screen. 2011 Dec;16(10):1153-69.
• [2] Sirtuin modulators: an updated patent review (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):5-15.
• [3] Sirtuin 1 activator SRT2104 protects Huntington's disease mice. Ann Clin Transl Neurol. 2014 Dec;1(12):1047-52.
• [4] Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy.PLoS One.2013 Jun 10;8(6):e64953.
• [5] SRT2379, a small-molecule SIRT1 activator, fails to reduce cytokine release in a human endotoxemia model. Critical Care 2013, 17(Suppl 4):P8.
• [6] The 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.
• [7] Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity. J Med Chem. 2009 May 14;52(9):2673-82.
• [8] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [9] Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J Med Chem. 2005 Dec 1;48(24):7789-95.
• [10] Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem. 2005 Dec 15;48(25):8045-54.
• [11] Characterization of sirtuin inhibitors in nematodes expressing a muscular dystrophy protein reveals muscle cell and behavioral protection by specif... J Med Chem. 2010 Feb 11;53(3):1407-11.
• [12] Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition. J Med Chem. 2006 Dec 14;49(25):7307-16.
• [13] Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6.
• [14] URL: 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).