Phosphatidylinositol-4-phosphate 5-kinase type-1 γ (PIP5K1C) is a lipid kinase that generates phosphatidylinositol-4,5-bisphosphate (PIP2) in nociceptive dorsal root ganglia (DRG). Pain sensitization is regulated by multiple signaling pathways that are initiated by phospholipase C-mediated hydrolysis of PIP2. UNC3230 is a small molecule inhibitor of PIP5K1C (IC50 = 41 nM, Kd = 51 nM). It does not inhibit any other lipid kinases that regulate phosphoinositide levels, including phosphatidylinositol 3-kinases. At 100 nM, UNC3230 decreases PIP2 membrane levels in cultured DRG neurons by 45% and significantly reduces calcium signaling. At 2 nM, it displays antinociceptive effects in mouse models of chronic pain when administered intrathecally or injected into inflamed hindpaw.
