PHT-427

PHT-427 is a novel small-molecule inhibitor of PDPK1/Akt signaling with significant antitumor activity and minimal toxicity in vivo. The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. PHT-427 binds selectively to the PH domain of AKT, causing apoptosis at low micromolar concentrations. And it also binds to the PH domain of PDPK1. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. PHT-427 induces apoptosis (IC50 = 6.3 μM), mainly on Akt Ser473 residue and less strongly on the Akt Thr308 residue without affecting total Akt protein expression. PHT-427 also shows antiproliferation in Panc-1 cells (IC50 = 65 μM).