NCT-504, a selective allosteric inhibitor of PIP4Kγ, exhibits an IC50 value of 15.8 μM. It holds promise for the investigation of Huntington's disease.

PIP4Kγ:15.8 μM (IC50)

NCT-504 does not affect the intrinsic ATP-hydrolytic activity of PIP4Kγ in the absence of the PI5P substrate and does not inhibit PIP4Kbeta, while only weakly inhibiting PIP4Kalpha's phosphorylation of PI5P, all confirmed at a concentration of 50 μM. Despite this specificity, NCT-504 notably increases levels of PI(3,5)P2, PI3P, and PI5P in mouse embryonic fibroblasts (MEFs) and enhances autophagy by inducing both autophagy initiation and the turnover rate of autophagic cargo without impairing MEF cell viability, even at concentrations of up to 10 μM over 12 hours. Furthermore, NCT-504 leads to a significant increase in autolysosome formation with a slight increase in autophagosomes, boosts autophagy flux, and decreases huntingtin protein levels in 293A cells. Additionally, it lowers mutant huntingtin (mHtt) protein levels in immortalized striatal cells from knock-in Huntington's disease (HD) mice. Western blot analysis on HEK293T cells treated with 5 and 10 μM of NCT-504 for 2 and 6 hours corroborated these findings, revealing induced autophagosome formation.