Target Information

Target General Information

Target ID

T03818 (Former ID: TTDR01386)

Target Name

PPAR-gamma messenger RNA (PPARG mRNA)

Synonyms

Transcription factor PPAR gamma receptor (mRNA); Peroxisome proliferator-activated receptor gamma (mRNA); PPARgamma (mRNA); PPAR-gamma (mRNA); Nuclear receptor subfamily 1 group C member 3 (mRNA); NR1C3 (mRNA)

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Gene Name

PPARG

Target Type

Literature-reported target

[1]

Disease

[+] 1 Target-related Diseases

Sjogren syndrome [ICD-11: 4A43]

Function

Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels. Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids.

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BioChemical Class

mRNA target

UniProt ID

PPARG_HUMAN

Sequence

MGETLGDSPIDPESDSFTDTLSANISQEMTMVDTEMPFWPTNFGISSVDLSVMEDHSHSF
DIKPFTTVDFSSISTPHYEDIPFTRTDPVVADYKYDLKLQEYQSAIKVEPASPPYYSEKT
QLYNKPHEEPSNSLMAIECRVCGDKASGFHYGVHACEGCKGFFRRTIRLKLIYDRCDLNC
RIHKKSRNKCQYCRFQKCLAVGMSHNAIRFGRMPQAEKEKLLAEISSDIDQLNPESADLR
ALAKHLYDSYIKSFPLTKAKARAILTGKTTDKSPFVIYDMNSLMMGEDKIKFKHITPLQE
QSKEVAIRIFQGCQFRSVEAVQEITEYAKSIPGFVNLDLNDQVTLLKYGVHEIIYTMLAS
LMNKDGVLISEGQGFMTREFLKSLRKPFGDFMEPKFEFAVKFNALELDDSDLAIFIAVII
LSGDRPGLLNVKPIEDIQDNLLQALELQLKLNHPESSQLFAKLLQKMTDLRQIVTEHVQL
LQVIKKTETDMSLHPLLQEIYKDLY

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Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Bardoxolone methyl

Drug Info

Phase 3

Mixed connective tissue disease

[2]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

AD-5075

Drug Info

Terminated

Type-2 diabetes

[3], [4]

Mode of Action

[+] 3 Modes of Action

Antagonist

[+] 2 Antagonist drugs

Bardoxolone methyl

Drug Info

[5]

T0070907

Drug Info

[7], [26]

Agonist

[+] 18 Agonist drugs

AD-5075

Drug Info

[4]

AD-5061

Drug Info

[8]

BADGE

Drug Info

[9]

COOH

Drug Info

[12]

DRF 2519

Drug Info

[13]

GW0072

Drug Info

[15]

GW1929

Drug Info

[16]

L-764406

Drug Info

[20]

L-783483

Drug Info

[21]

LG100754

Drug Info

[22]

nTzDpa

Drug Info

[23]

PAT5A

Drug Info

[24]

reglitazar

Drug Info

[25]

tagitinin A

Drug Info

[27]

tirotundin

Drug Info

[27]

TZD18

Drug Info

[28]

[125I]SB-236636

Drug Info

[29]

[3H]GW2331

Drug Info

[30]

Inhibitor

[+] 22 Inhibitor drugs

(9Z,12E)-12-nitrooctadeca-9,12-dienoic acid

Drug Info

[6]

(E)-10-nitrooctadec-9-enoic acid

Drug Info

[6]

(E)-12-Nitrooctadec-12-enoic Acid

Drug Info

[6]

(E)-13-Nitrooctadec-12-enoic Acid

Drug Info

[6]

(E)-5-Nitrooctadec-5-enoic Acid

Drug Info

[6]

(E)-9-Nitrohexadec-9-enoicAcid

Drug Info

[6]

(E)-9-nitrooctadec-9-enoic acid

Drug Info

[6]

2-chloro-5-nitro-N-phenylbenzamide

Drug Info

[7]

BRL-48482

Drug Info

[10]

CHLOROCYCLINONE A

Drug Info

[11]

CHLOROCYCLINONE B

Drug Info

[11]

CHLOROCYCLINONE C

Drug Info

[11]

GNF-PF-2893

Drug Info

[14]

GNF-PF-3037

Drug Info

[14]

L-165461

Drug Info

[19]

L-796449

Drug Info

[19]

L-Tryptophan-L-2-aminoadipic acid

Drug Info

[7]

L-Tryptophan-L-arginine

Drug Info

[7]

L-Tryptophan-L-asparagine

Drug Info

[7]

L-Tryptophan-L-aspartic acid

Drug Info

[7]

L-Tryptophan-L-glutamine

Drug Info

[7]

SB-213068

Drug Info

[10]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Profiles in Patients

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Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 7 KEGG Pathways

PPAR signaling pathway

AMPK signaling pathway

Osteoclast differentiation

Huntington's disease

Pathways in cancer

Transcriptional misregulation in cancer

Thyroid cancer

NetPath Pathway

[+] 3 NetPath Pathways

IL1 Signaling Pathway

TGF_beta_Receptor Signaling Pathway

Leptin Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

CCKR signaling map ST

PID Pathway

[+] 5 PID Pathways

Noncanonical Wnt signaling pathway

Calcineurin-regulated NFAT-dependent transcription in lymphocytes

Signaling events mediated by HDAC Class I

RXR and RAR heterodimerization with other nuclear receptor

Regulation of retinoblastoma protein

Reactome

[+] 3 Reactome Pathways

PPARA activates gene expression

Transcriptional regulation of white adipocyte differentiation

Nuclear Receptor transcription pathway

WikiPathways

[+] 8 WikiPathways

Wnt Signaling Pathway Netpath

Nuclear Receptors in Lipid Metabolism and Toxicity

Differentiation of white and brown adipocyte

Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)

Transcriptional Regulation of White Adipocyte Differentiation

Adipogenesis

SREBP signalling

Nuclear Receptors

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Benzoyl 2-methyl indoles as selective PPARgamma modulators. Bioorg Med Chem Lett. 2005 Jan 17;15(2):357-62.

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

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. (Ligand id: 2701).

REF 4

Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology. 1996 Oct;137(10):4189-95.

REF 5

A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma. Mol Endocrinol. 2000 Oct;14(10):1550-6.

REF 6

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by nitroalkene fatty acids: importance of nitration position and degree ... J Med Chem. 2009 Aug 13;52(15):4631-9.

REF 7

Tryptophan-containing dipeptide derivatives as potent PPARgamma antagonists: design, synthesis, biological evaluation, and molecular modeling. Eur J Med Chem. 2008 Dec;43(12):2699-716.

REF 8

A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes. Eur J Pharmacol. 2004 Jul 8;495(1):17-26.

REF 9

A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem. 2000 Jan 21;275(3):1873-7.

REF 10

Non thiazolidinedione antihyperglycaemic agents. 2: alpha-Carbon substituted beta-phenylpropanoic acids1, Bioorg. Med. Chem. Lett. 6(17):2127-2130 (1996).

REF 11

Chlorocyclinones A-D, chlorinated angucyclinones from Streptomyces sp. strongly antagonizing rosiglitazone-induced PPAR-gamma activation. J Nat Prod. 2007 Dec;70(12):1934-8.

REF 12

PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion.Diabetes. 2003 Feb;52(2):291-9.

REF 13

Antidiabetic and hypolipidemic potential of DRF 2519--a dual activator of PPAR-alpha and PPAR-gamma. Eur J Pharmacol. 2004 May 3;491(2-3):195-206.

REF 14

In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.

REF 15

A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6102-6.

REF 16

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes. 1999 Jul;48(7):1415-24.

REF 17

US patent application no. 6,159,734, Antisense modulation of peroxisome proliferator-activated receptor gamma expression.

REF 18

US patent application no. 7,425,545, Modulation of C-reactive protein expression.

REF 19

Phenylacetic acid derivatives as hPPAR agonists. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1277-80.

REF 20

L-764406 is a partial agonist of human peroxisome proliferator-activated receptor gamma. The role of Cys313 in ligand binding. J Biol Chem. 1999 Mar 19;274(12):7913-22.

REF 21

Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999 Mar 5;274(10):6718-25.

REF 22

The antidiabetic agent LG100754 sensitizes cells to low concentrations of peroxisome proliferator-activated receptor gamma ligands. J Biol Chem. 2002 Apr 12;277(15):12503-6.

REF 23

Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator. Mol Endocrinol. 2003 Apr;17(4):662-76.

REF 24

Euglycemic and hypolipidemic activity of PAT5A: a unique thiazolidinedione with weak peroxisome proliferator activated receptor gamma activity. Metabolism. 2000 Nov;49(11):1417-23.

REF 25

Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative. Eur J Pharmacol. 1999 Jan 8;364(2-3):211-9.

REF 26

T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. J Biol Chem. 2002 May 31;277(22):19649-57.

REF 27

Sesquiterpene lactones from Tithonia diversifolia act as peroxisome proliferator-activated receptor agonists. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2954-8.

REF 28

A novel peroxisome proliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis. Endocrinology. 2004 Apr;145(4):1640-8.

REF 29

Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J Pharmacol Exp Ther. 1998 Feb;284(2):751-9.

REF 30

Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4318-23.

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