Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTT1JVS)

• DTT Name: Cytosolic phospholipase A2 (GIVA cPLA2)
• Synonyms: Phospholipase A2 group IVA; PLA2G4; CPLA2
• Gene Name: PLA2G4A
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Carboxylic ester hydrolase
• UniProt ID: PA24A_HUMAN
• TTD ID: T14834
• Sequence:
  MSFIDPYQHIIVEHQYSHKFTVVVLRATKVTKGAFGDMLDTPDPYVELFISTTPDSRKRT
  RHFNNDINPVWNETFEFILDPNQENVLEITLMDANYVMDETLGTATFTVSSMKVGEKKEV
  PFIFNQVTEMVLEMSLEVCSCPDLRFSMALCDQEKTFRQQRKEHIRESMKKLLGPKNSEG
  LHSARDVPVVAILGSGGGFRAMVGFSGVMKALYESGILDCATYVAGLSGSTWYMSTLYSH
  PDFPEKGPEEINEELMKNVSHNPLLLLTPQKVKRYVESLWKKKSSGQPVTFTDIFGMLIG
  ETLIHNRMNTTLSSLKEKVNTAQCPLPLFTCLHVKPDVSELMFADWVEFSPYEIGMAKYG
  TFMAPDLFGSKFFMGTVVKKYEENPLHFLMGVWGSAFSILFNRVLGVSGSQSRGSTMEEE
  LENITTKHIVSNDSSDSDDESHEPKGTENEDAGSDYQSDNQASWIHRMIMALVSDSALFN
  TREGRAGKVHNFMLGLNLNTSYPLSPLSDFATQDSFDDDELDAAVADPDEFERIYEPLDV
  KSKKIHVVDSGLTFNLPYPLILRPQRGVDLIISFDFSARPSDSSPPFKELLLAEKWAKMN
  KLPFPKIDPYVFDREGLKECYVFKPKNPDMEKDCPTIIHFVLANINFRKYRAPGVPRETE
  EEKEIADFDIFDDPESPFSTFNFQYPNQAFKRLHDLMHFNTLNNIDVIKEAMVESIEYRR
  QNPSRCSVSLSNVEARRFFNKEFLSKPKA
• Function: Together with its lysophospholipid activity, it is implicated in the initiation of the inflammatory response. Selectively hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Arachidonic acid metabolism (hsa00590)
  Linoleic acid metabolism (hsa00591)
  alpha-Linolenic acid metabolism (hsa00592)
  Metabolic pathways (hsa01100)
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  Vascular smooth muscle contraction (hsa04270)
  VEGF signaling pathway (hsa04370)
  Platelet activation (hsa04611)
  Fc epsilon RI signaling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Glutamatergic synapse (hsa04724)
  Serotonergic synapse (hsa04726)
  Long-term depression (hsa04730)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  GnRH signaling pathway (hsa04912)
  Ovarian steroidogenesis (hsa04913)
  Oxytocin signaling pathway (hsa04921)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Acyl chain remodelling of PE (R-HSA-1482839)
  Acyl chain remodelling of PI (R-HSA-1482922)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  Platelet sensitization by LDL (R-HSA-432142)
  Acyl chain remodelling of PC (R-HSA-1482788)
• BioCyc Pathway: MetaCyc:HS04039-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ZPL521	DMPZE2G	Atopic dermatitis	EA80	Phase 1/2	[1]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
EFIPLADIB	DMJ0A5U	Asthma	CA23	Terminated	[2]

44 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(S)-Ethyl 6-(2-oxohexadecanamido)decanoate	DMFSXTJ	Discovery agent	N.A.	Investigative	[3]
(S)-Methyl 4-(2-oxohexadecanamido)octanoate	DM8H0ND	Discovery agent	N.A.	Investigative	[3]
(S)-tert-Butyl 4-(2-oxohexadecanamido)pentanoate	DMLG8Q2	Discovery agent	N.A.	Investigative	[3]
(Z)-1,1,1,2,2,3,3-heptafluorohenicos-12-en-4-one	DMSVBZO	Discovery agent	N.A.	Investigative	[4]
1,1,1,2,2,3,3,5-octafluoro-8-phenyloctan-4-one	DMWHN2J	Discovery agent	N.A.	Investigative	[4]
1,1,1,2,2,3,3-heptafluoro-8-phenyloctan-4-ol	DM45NF1	Discovery agent	N.A.	Investigative	[4]
1,1,1,2,2,4-hexafluoro-7-phenylheptan-3-one	DMN68K4	Discovery agent	N.A.	Investigative	[4]
1,1,1,2,2-Pentafluoro-8-phenyl-octan-3-one	DM7U8LD	Discovery agent	N.A.	Investigative	[5]
1,1,1,2,2-Pentafluoro-9-phenyl-nonan-3-one	DMSEHNV	Discovery agent	N.A.	Investigative	[5]
1,1,1,3-Tetrafluoro-6-phenylhexan-2-one	DMLDH4Z	Discovery agent	N.A.	Investigative	[4]
1,1,1,3-Tetrafluoro-7-phenylheptan-2-one	DMV0CXN	Discovery agent	N.A.	Investigative	[4]
1,1,1,3-Tetrafluoro-heptadecan-2-one	DMD36WS	Discovery agent	N.A.	Investigative	[5]
1,1,1-Trifluoro-4-(4-hexyloxy-phenyl)-butan-2-one	DMODCAM	Discovery agent	N.A.	Investigative	[5]
1,1,1-Trifluoro-5-(4-octylphenoxy)pentan-2-one	DMI2XWY	Discovery agent	N.A.	Investigative	[4]
1,1,1-Trifluoro-6-(4-hexyloxy-phenyl)-hexan-2-one	DMCAQ5T	Discovery agent	N.A.	Investigative	[5]
1,1,1-Trifluoro-6-(naphthalen-2-yl)hexan-2-one	DMZ2VE3	Discovery agent	N.A.	Investigative	[4]
1,1,1-Trifluoro-7-phenylheptan-2-one	DMLHVWP	Discovery agent	N.A.	Investigative	[5]
1,1,1-Trifluoro-8-phenyl-octan-2-one	DMYENI7	Discovery agent	N.A.	Investigative	[5]
1,1,1-trifluoroheptadecan-2-one	DMB5U3P	Discovery agent	N.A.	Investigative	[5]
1-Imidazol-1-yl-3-(4-octylphenoxy)propan-2-one	DM3JHVL	Discovery agent	N.A.	Investigative	[6]
4-(2-oxohexadecanamido)butanoic acid	DMBMJC5	Discovery agent	N.A.	Investigative	[7]
4-(4-Decyloxy-phenyl)-1,1,1-trifluoro-butan-2-one	DMCDKHJ	Discovery agent	N.A.	Investigative	[5]
6-(4-Decyloxy-phenyl)-1,1,1-trifluoro-hexan-2-one	DMYQB5R	Discovery agent	N.A.	Investigative	[5]
Allyl 4-(2-oxohexadecanamido)butanoate	DM8R5AS	Discovery agent	N.A.	Investigative	[3]
AR-C70484XX	DMU3A57	Discovery agent	N.A.	Investigative	[6]
ARACHIDONYL TRIFLUOROMETHYLKETONE	DMHL48F	Discovery agent	N.A.	Investigative	[8]
AX-006	DMDWCY7	Discovery agent	N.A.	Investigative	[9]
AX-048	DMIDXSN	Discovery agent	N.A.	Investigative	[9]
ECOPLADIB	DMWKS29	Discovery agent	N.A.	Investigative	[2]
Ethyl 2-(2-oxohexadecanamido)acetate	DM762HQ	Discovery agent	N.A.	Investigative	[3]
Ethyl 4-(2-oxohexadecanamido)benzoate	DMB12M7	Discovery agent	N.A.	Investigative	[3]
Methyl 2-(2-oxo-8-phenyloctanamido)acetate	DMBKU9M	Discovery agent	N.A.	Investigative	[3]
Methyl 2-(2-oxohexadecanamido)acetate	DMVYGBU	Discovery agent	N.A.	Investigative	[3]
Methyl arachidonyl fluorophosphonate	DMAXEH3	Discovery agent	N.A.	Investigative	[8]
N-(4-Ethoxybutyl)-2-oxohexadecanamide	DM012TN	Discovery agent	N.A.	Investigative	[3]
Tert-Butyl 2-(2-oxohexadecanamido)acetate	DMWQFY6	Discovery agent	N.A.	Investigative	[3]
Tert-Butyl 3-(2-oxo-8-phenyloctanamido)propanoate	DMNU9WV	Discovery agent	N.A.	Investigative	[3]
Tert-Butyl 3-(2-oxohexadecanamido)propanoate	DMYQXPB	Discovery agent	N.A.	Investigative	[3]
Tert-Butyl 5-(2-oxohexadecanamido)pentanoate	DM1ALTR	Discovery agent	N.A.	Investigative	[3]
WAY-196025	DMNH0CM	Discovery agent	N.A.	Investigative	[2]
[3,4''']biflavone	DMHU4NS	Discovery agent	N.A.	Investigative	[10]
[4',4''']-biflavone	DM7JSQL	Discovery agent	N.A.	Investigative	[10]
[6,3''']biflavone	DMA9PW7	Discovery agent	N.A.	Investigative	[10]
[6,4''']biflavone	DMVOX4L	Discovery agent	N.A.	Investigative	[10]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Cytosolic phospholipase A2 (PLA2G4A) DME Info
• Gene Name: PLA2G4A

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Urethane	DM7NSI0	N. A.	N. A.	Phase 4	[11]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Reactions of functionalized sulfonamides: application to lowering the lipophilicity of cytosolic phospholipase A2alpha inhibitors. J Med Chem. 2009 Feb 26;52(4):1156-71.
• [3] Structure-activity relationships of natural and non-natural amino acid-based amide and 2-oxoamide inhibitors of human phospholipase A(2) enzymes. Bioorg Med Chem. 2008 Dec 15;16(24):10257-69.
• [4] Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2. J Med Chem. 2010 May 13;53(9):3602-10.
• [5] Synthesis of polyfluoro ketones for selective inhibition of human phospholipase A2 enzymes. J Med Chem. 2008 Dec 25;51(24):8027-37.
• [6] 1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A(2)alpha and fatty acid amide hydrolase. Bioorg Med Chem. 2010 Jan 15;18(2):945-52.
• [7] Discovery of Ecopladib, an indole inhibitor of cytosolic phospholipase A2alpha. J Med Chem. 2007 Mar 22;50(6):1380-400.
• [8] 85-kDa cPLA(2) plays a critical role in PPAR-mediated gene transcription in human hepatoma cells. Am J Physiol Gastrointest Liver Physiol. 2002 Apr;282(4):G586-97.
• [9] 2-Oxoamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudodipeptides. Bioorg Med Chem. 2009 Jul 1;17(13):4833-43.
• [10] Inhibitory effect of synthetic C-C biflavones on various phospholipase A(2)s activity. Bioorg Med Chem. 2007 Nov 15;15(22):7138-43.
• [11] Phospholipase A2 pathway association with macrophage-mediated polycarbonate-urethane biodegradation. Biomaterials. 2005 Jun;26(18):3881-9.