Summary of the probe development effort to identify inhibitors of phospholipase C isozymes (PLC-beta 3).
Name: Summary of the probe development effort to identify inhibitors of phospholipase C isozymes (PLC-beta 3). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Center Affiliation: The Scripps Research Institute
Assay Provider: Qisheng Zhang, University of North Carolina at Chapel Hill
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: R01GM098894
Grant Proposal PI: Qisheng Zhang, University of North Carolina at Chapel Hill
External Assay ID: PLCB3_INH_SUMMARY
Name: Summary of the probe development effort to identify inhibitors of phospholipase C isozymes (PLC-beta 3).
Extracellular stimuli including hormones, growth factors, and neurotransmitters promote activation of phospholipase C (PLC) isozymes and cleavage of the membrane lipid phosphatidylinositol 4,5- bisphosphate (PtdIns(4,5)P2) into the classical second messengers, diacylglycerol and inositol 1,4,5- trisphosphate (IP3) . These second messengers coordinately control numerous signaling cascades through the mobilization of intracellular Ca2+ stores and the activation of protein kinase C. Aberrant regulation of PLCs contribute to diverse human diseases including cancer [2-4], cardiovascular diseases [5-6], and neuropathic pain , as well as schizophrenia and epilepsy [5, 8-9]. Consequently, small molecule PLC inhibitors will be valuable pharmacological tools to dissect the roles of PLCs in development and disease, and could potentially serve as candidates for drug development.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of phospholipase C isozymes (PLC-B3). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
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2. Bertagnolo, V., et al., Phospholipase C-beta 2 promotes mitosis and migration of human breast cancer-derived cells. Carcinogenesis, 2007. 28(8): p. 1638-45.
3. Sala, G., et al., Phospholipase Cgamma1 is required for metastasis development and progression. Cancer Res, 2008. 68(24): p. 10187-96
4. Shepard, C.R., et al., PLC gamma contributes to metastasis of in situ-occurring mammary and prostate tumors. Oncogene, 2007. 26(21): p. 3020-6.
5. Woodcock, E.A., D.R. Grubb, and P. Iliades, Potential treatment of cardiac hypertrophy and heart failure by inhibiting the sarcolemmal binding of phospholipase Cbeta1b. Curr Drug Targets, 2010. 11(8): p. 1032-40.
6. Zhang, L., et al., Phospholipase C epsilon scaffolds to muscle-specific A kinase anchoring protein (mAKAPbeta) and integrates multiple hypertrophic stimuli in cardiac myocytes. J Biol Chem, 2011. 286(26): p. 23012-21.
7. Kurian, M.A., et al., Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain, 2010. 133(10): p. 2964-70.
8. Hinkes, B., et al., Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet, 2006. 38(12): p. 1397-405.
9. McOmish, C.E., et al., PLC-beta1 knockout mice as a model of disrupted cortical development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression. Hippocampus, 2008. 18(8): p. 824-34.
10. Bala, G.A., N.R. Thakur, and J.E. Bleasdale, Characterization of the major phosphoinositide-specific phospholipase C of human amnion. Biol Reprod, 1990. 43(4): p. 704-11.
11. Bleasdale, J.E., et al., Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils. J Pharmacol Exp Ther, 1990. 255(2): p. 756-68.
12. Berven, L.A. and G.J. Barritt, Evidence obtained using single hepatocytes for inhibition by the phospholipase C inhibitor U73122 of store-operated Ca2+ inflow. Biochem Pharmacol, 1995. 49(10): p. 1373-9.
13. Hollywood, M.A., et al., The PI-PLC inhibitor U-73122 is a potent inhibitor of the SERCA pump in smooth muscle. Br J Pharmacol, 2010. 160(6): p. 1293-4.
14. Pulcinelli, F.M., et al., Evidence for separate effects of U73122 on phospholipase C and calcium channels in human platelets. Biochem Pharmacol, 1998. 56(11): p. 1481-4.
15. Wang, J.P., U-73122, an aminosteroid phospholipase C inhibitor, may also block Ca2+ influx through phospholipase C-independent mechanism in neutrophil activation. Naunyn Schmiedebergs Arch Pharmacol, 1996. 353(6): p. 599-605.
16. Wilsher, N.E., et al., The phosphoinositide-specific phospholipase C inhibitor U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-d ione) spontaneously forms conjugates with common components of cell culture medium. Drug Metab Dispos, 2007. 35(7): p. 1017-22.
17. Burgdorf, C., et al., U73122, an aminosteroid phospholipase C inhibitor, is a potent inhibitor of cardiac phospholipase D by a PIP2-dependent mechanism. J Cardiovasc Pharmacol, 2010. 55(6): p. 555-9.
18. Feisst, C., et al., The aminosteroid phospholipase C antagonist U-73122 (1-[6-[[17-beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5- dione) potently inhibits human 5-lipoxygenase in vivo and in vitro. Mol Pharmacol, 2005. 67(5): p. 1751-7.
19. Vickers, J.D., U73122 affects the equilibria between the phosphoinositides as well as phospholipase C activity in unstimulated and thrombin-stimulated human and rabbit platelets. J Pharmacol Exp Ther, 1993. 266(3): p. 1156-63.
20. Klein, R.R., et al., Direct activation of human phospholipase C by its well known inhibitor u73122. J Biol Chem, 2011. 286(14): p. 12407-16.
Summary, Summary AID, phospholipase C, PLCs, PLCB3, PLC-beta 3, WH-15, fluorogenic reporter, Cholate, biochemical, inhibition, modulators, isozymes, cancer, neurotransmitters, 6-aminoquinoline, quinomethide derivative, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC inhibitor, fluorescence, HTS, Molecular Libraries Probe Production Centers Network, MLPCN