Summary of the probe development efforts to identify inhibitors of human platelet activating factor acetylhydrolase 2 (PAFAH2)
Name: Summary of the probe development efforts to identify inhibitors of human platelet activating factor acetylhydrolase 2 (PAFAH2). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Brian J. Bahnson, University of Delaware
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: HL084366
Grant Proposal PI: Brian J. Bahnson, University of Delaware
External Assay ID: PAFAH2_INH_SUMMARY
Name: Summary of the probe development efforts to identify inhibitors of human platelet activating factor acetylhydrolase 2 (PAFAH2).
Atherosclerosis is a process in which plaques, deposits of low density lipoproteins (LDL), lipid-laden macrophages and other inflammatory cells, calcium, and cellular debris build up in the inner lining of an artery. These plaques interfere with blood flow, damage the arterial wall, and eventually rupture, causing debris to migrate downstream, leading to myocardial infarction or stroke (1-4). Human platelet activating factor acetylhydrolase (pPAFAH) is a Ca2+ independent phospholipase A2 (PLA2) identified in human plasma as the enzyme responsible for the hydrolysis/inactivation of platelet activating factor (PAF) (5, 6), a potent pro-inflammatory phospholipid signaling molecule (7). PAFAH catalyses the hydrolysis of the acetyl group at the sn-2 position of the glycerol backbone of PAF converting it to lyso-PAF (8-9). PAFAH has a catalytic cysteine residue and is consequently sensitive to broadly reactive thiol alkylating agents, including N-ethylmaleimide (10); however, selective inhibitors for PAFAH have not yet been identified. Inhibiting PAFAH may thus offer a new therapeutic strategy for cancer. Development of a selective inhibitor would also aid in the investigation into PAFAH involvement in the dysregulated biochemical pathways that support tumorigenesis. As a result, the identification of inhibitors of PAFAH would help to elucidate the physiological role of this enzyme and its contribution to atherosclerosis, cancer, and other inflammatory pathologies (11).
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of human platelet activating factor acetylhydrolase 2 (PAFAH2). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Karasawa, K., Harada, A., Satoh, N., Inoue, K., and Setaka, M. (2003) Plasma platelet activating factor acetylhydrolase (PAF-AH), Prog Lipid Res 42, 93-114.
2. Leitinger, N. (2005) Oxidized phospholipids as triggers of inflammation in atherosclerosis, Molecular Nutrition & Food Research 49, 1063-1071.
3. Blank, M. L., Lee, T., Fitzgerald, V., and Snyder, F. (1981) A specific acetylhydrolase for 1-alkyl-2- acetyl-sn glycero-3-phosphocholine (a hypotensive and platelet-activating lipid), J Biol Chem 256, 175-178.
4. Farr, R. S., Cox, C. P., Wardlow, M. L., and Jorgensen, R. (1980) Preliminary studies of an acid labile factor (ALF) in human sera that inactivates platelet-activating factor (PAF), Clin Immunol Immunopathol 15, 318-330.
5. Zimmerman, G. A., McIntyre, T. M., Prescott, S. M., and Stafforini, D. M. (2002) The plateletactivating factor signaling system and its regulators in syndromes of inflammation and thrombosis, Crit Care Med 30, S294-301.
6. Anderson, J. L. (2008) Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention, Am J Cardiol 101, 23F-33F.
7. Sudhir, K. (2005) Clinical review: Lipoprotein-associated phospholipase A2, a novel inflammatory biomarker and independent risk predictor for cardiovascular disease, J Clin Endocrinol Metab 90, 3100-3105.
8. Wilensky, R. L., and Macphee, C. H. (2009) Lipoprotein-associated phospholipase A(2) and atherosclerosis, Curr Opin Lipidol 20, 415-420.
9. Karabina, S. A., and Ninio, E. (2006) Plasma PAF-acetylhydrolase: an unfulfilled promise?, Biochim Biophys Acta 1761, 1351-1358.
10. Samanta, U., and Bahnson, B. J. (2008) Crystal structure of human plasma platelet-activating factor acetylhydrolase: structural implication to lipoprotein binding and catalysis, J Biol Chem 283, 31617-31624.
11. Blackie, J. A., Bloomer, J. C., Brown, M. J. B., Cheng, H. Y., Hammond, B., Hickey, D. M. B., Ife, R. J., Leach, C. A., Lewis, V. A., Macphee, C. H., Milliner, K. J., Moores, K. E., Pinto, I. L., Smith, S. A., Stansfield, I. G., Stanway, S. J., Taylor, M. A., and Theobald, C. J. (2003) The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A(2), Bioorganic & Medicinal Chemistry Letters 13, 1067-1070.
Summary, Summary AID, FLJ26025; HSD-PLA2, PAFAH2, 40kDa, pPAFAH, PAFAH1b2, PAFAH1b3, hydrolase, lipase, platelet activating factor acetylhydrolase 2, FP-Rh, atherosclerosis, heart disease, fluorescence polarization, FP, fluorescence, inhibit, inhibition, inhibitor, primary, primary screen, HTS, 1536, Scripps, Scripps Florida, Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
§ Panel component ID.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML225
PubChem Substance ID (SID) for probe 1: 103913572
PubChem Compound ID (CID) for probe 1: 56593029
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 3
Target for probe 1: PAFAH2 (gi: 4758878)
Anti-target for probe 1: >20 SHs, pPAFAH
Fold selectivity for probe 1: >333, >33
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK133429/ (ID: 3025210)
Grant number for probe 1: HL084366
PubMed Publication ID (PMID) for probe 1: 23260346
NCBI Book chapter title for probe 1: Optimization and characterization of a triazole urea inhibitor for platelet-activating factor acetylhydrolase type 2 (PAFAH2)
* Activity Concentration. § Panel component ID.