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PLA2-G7

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1432

Nomenclature: PLA2-G7

Family: Phospholipase A2, Hydrolases & Lipases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 441 6p12.3 PLA2G7 phospholipase A2 group VII
Mouse - 440 17 B3 Pla2g7 phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
Rat - 440 9q12 Pla2g7 phospholipase A2 group VII
Previous and Unofficial Names Click here for help
GVII | platelet-activating factor acetylhydrolase | PAF acetylhydrolase | LDL-PLA2 | LDL-associated phospholipase A2 | PAFAH | phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) | phospholipase A2
Database Links Click here for help
Alphafold Q13093 (Hs), Q60963 (Mm)
BRENDA 3.1.1.4
CATH/Gene3D 3.40.50.1820
ChEMBL Target CHEMBL3514 (Hs), CHEMBL5383 (Mm)
Ensembl Gene ENSG00000146070 (Hs), ENSMUSG00000023913 (Mm), ENSRNOG00000025691 (Rn)
Entrez Gene 7941 (Hs), 27226 (Mm), 301265 (Rn)
Human Protein Atlas ENSG00000146070 (Hs)
KEGG Enzyme 3.1.1.4
KEGG Gene hsa:7941 (Hs), mmu:27226 (Mm), rno:301265 (Rn)
OMIM 601690 (Hs)
Pharos Q13093 (Hs)
RefSeq Nucleotide NM_005084 (Hs), NM_013737 (Mm), NM_001009353 (Rn)
RefSeq Protein NP_005075 (Hs), NP_038765 (Mm), NP_001009353 (Rn)
SynPHARM 84828 (in complex with darapladib)
84827 (in complex with darapladib)
78680 (in complex with darapladib)
84830 (in complex with (S)-23 [PMID: 27933945])
84829 (in complex with (S)-23 [PMID: 27933945])
UniProtKB Q13093 (Hs), Q60963 (Mm)
Wikipedia PLA2G7 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Fragment-based inhibitors of Lipoprotein associated Phospholipase A2.
PDB Id:  5LZ9
Ligand:  (S)-23 [PMID: 27933945]
Resolution:  2.06Å
Species:  Human
References:  7
Enzyme Reaction Click here for help
EC Number: 3.1.1.4

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
rilapladib Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Competitive 9.6 pIC50 6
⤷ pIC50 9.6 (IC50 2.3x10-10 M) [6]
darapladib Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 – 10.3 pIC50 1,7
⤷ pIC50 10.3 (IC50 4.9x10-11 M) [7]
Description: In a biochemical assay, measuring fluorescence intensity and using Thio-Paf.
pIC50 10.0 (IC50 1.1x10-10 M) [1]
pIC50 7.5 (IC50 3.5x10-8 M) [7]
Description: In an assay using whole human plasma and recombinant hPLA2-G7, that approximates the physiological environment of the enzyme.
compound 37 [PMID: 29193967] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.8 pIC50 4
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [4]
(S)-23 [PMID: 27933945] Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.9 – 7.5 pIC50 7
⤷ pIC50 7.5 (IC50 3.2x10-8 M) [7]
Description: Recombinant hLp-PLA2 in a whole human plasma Thio-PAF assay.
pIC50 6.9 (IC50 1.2x10-7 M) [7]
Description: Recombinant hLp-PLA2 Thio-PAF biochemical assay.
ABX-1431 Small molecule or natural product Click here for species-specific activity table Hs Inhibition <5.0 pIC50 2
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [2]
Immunopharmacology Comments
PLA2-G7 (also referred to as Lp-PLA2) is a pro-inflammatory enzyme. It cleaves oxidatively damaged phospholipid substrates to generate pro-inflammatory mediators including lysophosphatidylcholine and oxidized nonesterified fatty acids [5] and this activity has been linked to atherogenesis and cardiovascular disease. PLA2-G7 has been investigated as a CVD drug target, with one clinical candidate (darapladib) failing in Phase 3 trials. In addition, polymorphisms in the PLA2G7 gene are associated with atopy and asthma [3]. The search for drug-like PLA2-G7 inhibitors with alternative chemotypes to darapladib is continuing [4,7].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Asthma, susceptibility to
Disease Ontology: DOID:2841
OMIM: 600807
Disease:  IgE responsiveness, atopic; IGER
OMIM: 147050
Disease:  Platelet-activating factor acetylhydrolase deficiency
OMIM: 614278

References

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1. Blackie JA, Bloomer JC, Brown MJ, Cheng HY, Hammond B, Hickey DM, Ife RJ, Leach CA, Lewis VA, Macphee CH et al.. (2003) The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett, 13 (6): 1067-70. [PMID:12643913]

2. Cisar JS, Weber OD, Clapper JR, Blankman JL, Henry CL, Simon GM, Alexander JP, Jones TK, Ezekowitz RAB, O'Neill GP et al.. (2018) Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders. J Med Chem, 61 (20): 9062-9084. [PMID:30067909]

3. Kruse S, Mao XQ, Heinzmann A, Blattmann S, Roberts MH, Braun S, Gao PS, Forster J, Kuehr J, Hopkin JM et al.. (2000) The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am J Hum Genet, 66 (5): 1522-30. [PMID:10733466]

4. Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y. (2017) Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2. J Med Chem, 60 (24): 10231-10244. [PMID:29193967]

5. MacPhee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA, Leake DS, Milliner KJ, Patterson RA, Suckling KE et al.. (1999) Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem J, 338 ( Pt 2): 479-87. [PMID:10024526]

6. Wilensky RL, Macphee CH. (2009) Lipoprotein-associated phospholipase A(2) and atherosclerosis. Curr Opin Lipidol, 20 (5): 415-20. [PMID:19667981]

7. Woolford AJ, Day PJ, Bénéton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES et al.. (2016) Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2). J Med Chem, 59 (23): 10738-10749. [PMID:27933945]

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