UNC3230 is a Selective and ATP-Competitive PIP5K1C Inhibitor

Phosphatidylinositol-4-phosphate 5-kinase type-1C (PIP5K1C) is a lipid kinase that regulates focal adhesion dynamics and cell attachment through the site-specific formation of phosphatidylinositol ,5-bisphosphate (PI4,5P2). Numerous pain-producing (pronociceptive) receptors signal via phosphatidylinositol 4,5- bisphosphate (PI4,5P2) hydrolysis. In this study, researchers found that PIP5K1C is expressed at higher levels than any other PIP5K. Researchers identified a small molecule inhibitor of PIP5K1C (UNC3230) in a high-throughput screen.

PIP5K1C regulates PIP2- dependent nociceptive signaling and suggest that PIP5K1C is a potential therapeutic target for chronic pain. UNC3230 is a selective small-molecule PIP5K1C inhibitor. UNC3230 has an IC50 of ~41 nM using the microfluidic mobility shift assay. Notably, UNC3230 does not interact with PIP5K1A at 10 μM. UNC3230 shows selectivity (Kd <0.2 μM; using competitive binding assays) for PIP5K1C and PIP4K2C. Moreover, UNC3230 does not inhibit any of the other lipid kinases that regulate phosphoinositide levels, including PI3Ks.

UNC3230 (100 nM) significantly reduces membrane PIP2 levels by ~45% in dorsal root ganglia neurons relative to vehicle controls. Especially, UNC3230 significantly reduces lysophosphatidic acid-evoked calcium signaling in cultured DRG neurons relative to vehicle. UNC3230 reduces membrane PIP2 levels in DRG neurons and GPCR signaling. In particular, UNC3230 has antinociceptive effects when injected intrathecally or into an inflamed hindpaw. UNC3230 reduces thermal and mechanical sensitization in models of chronic pain.

Tissue inflammation and nerve injury cause the release of a complex mix of chemicals that sensitize nociceptive dorsal root ganglia neurons and contribute to chronic pain. UNC3230 significantly reduces existing complete Freund’s adjuvant-induced thermal hyperalgesia relative to vehicle control. Moreover, UNC3230 significantly inhibits colorectal cancer glycolysis and tumor growth. All in all, UNC3230 is an inhibitor of the lipid kinase PIP5K1C.

Wright BD, et al. The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron. 2014 May 21;82(4):836-47.