Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT2JWF6)

• DTT Name: Peroxisome proliferator-activated receptor delta (PPARD)
• Synonyms: Peroxisomeproliferator-activated receptor beta; Peroxisomeproliferator activated receptor beta/delta; Peroxisome proliferator-activated receptor beta; PPARdelta; PPARB; PPAR-delta; PPAR-beta; Nuclear receptor subfamily 1 group C member 2; Nuclear hormone receptor 1; NUCI; NUC1; NR1C2
• Gene Name: PPARD
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: PPARD_HUMAN
• TTD ID: T36557
• Sequence:
  MEQPQEEAPEVREEEEKEEVAEAEGAPELNGGPQHALPSSSYTDLSRSSSPPSLLDQLQM
  GCDGASCGSLNMECRVCGDKASGFHYGVHACEGCKGFFRRTIRMKLEYEKCERSCKIQKK
  NRNKCQYCRFQKCLALGMSHNAIRFGRMPEAEKRKLVAGLTANEGSQYNPQVADLKAFSK
  HIYNAYLKNFNMTKKKARSILTGKASHTAPFVIHDIETLWQAEKGLVWKQLVNGLPPYKE
  ISVHVFYRCQCTTVETVRELTEFAKSIPSFSSLFLNDQVTLLKYGVHEAIFAMLASIVNK
  DGLLVANGSGFVTREFLRSLRKPFSDIIEPKFEFAVKFNALELDDSDLALFIAAIILCGD
  RPGLMNVPRVEAIQDTILRALEFHLQANHPDAQYLFPKLLQKMADLRQLVTEHAQMMQRI
  KKTETETSLHPLLQEIYKDMY
• Function: Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand. Ligand-activated transcription factor.
• KEGG Pathway:
  PPAR signaling pathway (hsa03320)
  Wnt signaling pathway (hsa04310)
  Pathways in cancer (hsa05200)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway:
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Import of palmitoyl-CoA into the mitochondrial matrix (R-HSA-200425)

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
GFT-505	DM7ZOAE	Non-alcoholic steatohepatitis	DB92.1	Phase 3	[2]
MBX-8025	DMNTCV4	Obesity	5B81	Phase 2/3	[3]
T3D-959	DMR3245	Alzheimer disease	8A20	Phase 2	[4]
CER-002	DMLBKZV	Dyslipidemia	5C80-5C81	Phase 1	[5]
KD3010	DMNFDYE	Metabolic disorder	5C50-5D2Z	Phase 1	[6]
SAR351034	DM15PG9	Dyslipidemia	5C80-5C81	Phase 1	[7]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID25416646-Compound-Figure5-C	DM17FKL	N. A.	N. A.	Patented	[8]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GW-501516	DMPL2KM	Type-1 diabetes	5A10	Discontinued in Phase 4	[1]
GSK-677954	DM5WRJX	Non-alcoholic fatty liver disease	DB92	Discontinued in Phase 2	[9]
Indeglitazar	DMS56UD	Type-2 diabetes	5A11	Discontinued in Phase 2	[10]
Sodelglitazar	DMJ816F	Hyperlipidaemia	5C80	Discontinued in Phase 2	[11]
CS-204	DM1E7H3	Metabolic disorder	5C50-5D2Z	Terminated	[12]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
KD-3020	DMIQXEP	Non-alcoholic fatty liver disease	DB92	Preclinical	[9]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(11E)-OCTADEC-11-ENOIC ACID	DMZ5YMH	Discovery agent	N.A.	Investigative	[13]
DB-900	DMGRUN1	Type-2 diabetes	5A11	Investigative	[14]
GSK-0660	DMNIVOX	Discovery agent	N.A.	Investigative	[15]
GSK-3787	DMKDLB7	Discovery agent	N.A.	Investigative	[15]
GW0742X	DMGKEO5	Discovery agent	N.A.	Investigative	[16]
GW2433	DMEAIQC	Discovery agent	N.A.	Investigative	[17]
Heptyl-Beta-D-Glucopyranoside	DMPQBN0	Discovery agent	N.A.	Investigative	[13]
L-165041	DMZP7YM	Discovery agent	N.A.	Investigative	[18]
L-165461	DMKBSGN	Discovery agent	N.A.	Investigative	[19]
L-783483	DM6OTGE	Discovery agent	N.A.	Investigative	[18]
L-796449	DMWTGQM	Discovery agent	N.A.	Investigative	[19]
SAVX-1	DMF8O62	Central nervous system disease	8A04-8D87	Investigative	[20]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	3.78E-01	9.87E-03	0.06
Non-alcoholic fatty liver disease	DD91.0	Liver tissue	1.25E-01	0.15	0.88
Type 2 diabetes	5A11	Liver tissue	1.47E-01	-0.07	-0.85
Coronary artery disease	BA80-BA8Z	Peripheral blood	7.87E-01	-0.05	-0.35

References

• [1] Lipid effects of peroxisome proliferator-activated receptor- agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome.Arterioscler Thromb Vasc Biol.2012 Sep;32(9):2289-94.
• [2] Dual peroxisome proliferator-activated receptor / agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.Diabetes Care.2013 Oct;36(10):2923-30.
• [3] ClinicalTrials.gov (NCT00701883) Safety and Benefit of MBX-8025 With and Without Commonly Used Statins in Moderately Overweight Patients With High Cholesterol. U. S. National Institute of Health. 2008.
• [4] Phrma report (2013 Alzheimers disease)
• [5] Fibrates, glitazones, and peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol. 2010 May; 30(5): 894-899.
• [6] Kalypsys nearing completion of phase Ia study of KD3010 for metabolic disorders. Kalypsys. 2007.
• [7] Addressing Unmet Medical Needs in Type 2 Diabetes: A Narrative Review of Drugs under Development. Curr Diabetes Rev. 2015 March; 11(1): 17-31.
• [8] PPAR ligands and their therapeutic applications: a patent review (2008 - 2014).Expert Opin Ther Pat. 2015 Feb;25(2):175-91.
• [9] Emerging drugs for non-alcoholic fatty liver disease. Expert Opin Emerg Drugs. 2008 Mar;13(1):145-58.
• [10] Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):262-7.
• [11] Docking and molecular dynamics simulations of peroxisome proliferator activated receptors interacting with pan agonist sodelglitazar. Protein Pept Lett. 2011 Oct;18(10):1021-7.
• [12] Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders. PPAR Res. 2008; 2008: 679137.
• [13] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [14] CN patent application no. 102459215, 3-(4-aminophenyl)-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof.
• [15] Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversibl... J Med Chem. 2010 Feb 25;53(4):1857-61.
• [16] Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity. Bioorg Med Chem Lett. 2003 May 5;13(9):1517-21.
• [17] Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chem Biol. 1997 Dec;4(12):909-18.
• [18] Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999 Mar 5;274(10):6718-25.
• [19] Phenylacetic acid derivatives as hPPAR agonists. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1277-80.
• [20] 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: 594).