Wortmannin, a Potent and Selective Inhibitor of Phosphatidylinositol-3-kinase
Abstract
Phosphatidylinositol-3-kinase is an important enzyme for intracellular signaling. The microbial product worthmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. The 50% inhibitory concentration for inhibition by wortmannin is 2 to 4 n M . Kinetic analysis demonstrates that wortmannin is a noncompetitive, irreversible inhibitor of phosphatidylinositol-3-kinase, with inactivation being both time- and concentration-dependent. Wortmannin has previously been reported to be an inhibitor of myosin light chain kinase but with an inhibitory concentration of 0.2 µ M . Wortmannin was found not to be an inhibitor of phosphatidylinositol-4-kinase, protein kinase C, or protein tyrosine kinase. Wortmannin inhibited the formation of phosphatidylinositol-3-phosphates in intact cells. The results of the study suggest that wortmannin and its analogues may have utility as pharmacological probes for studying the actions of phosphatidylinositol-3-kinase. 1 Work in the laboratories of G.P., R.A., C.A. and L.Z. supported by NCI Grant CA52995. 2 To whom requests for reprints should be addressed, at Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724