Modulators of lysophosphatidic acid signalling

Lysophosphatidic acid (LPA) is a key lipid mediator in the regulation of cell proliferation, cell survival, motility, invasion and wound healing in normal cells, such as fibroblasts and haematopoietic cells. In addition, LPA signalling is implicated in cancer, atherosclerosis, ischaemia perfusion injury and other pathophysiological conditions. LPA, sphingolipids and other lysophospholipids act through several mechanisms: (i) a family of cell-surface seven transmembrane domain G-protein-coupled receptors; (ii) a nuclear hormone-activated transcription factor; (iii) membrane curvature and endocytosis and (iv) other targets yet to be defined. Based on the action of LPA on molecular targets in different human pathologies, both receptor-selective agonists and antagonists are sought as potential clinical agents. In addition, the control of endogenous production and clearance of LPA may provide an important target for treatment of multiple disease states. Thus, modifiers of phospholipase A₁ and A₂, lysophospholipase D, LPA acyl transferase and lipid phosphate phosphatase activities should be explored as potential therapeutics. This overview summarises the literature and issued patents covering the molecular agents developed to potentially manipulate the specific effects of LPA on cell physiology and clinical outcome.