THE INHIBITION OF PHOSPHATIDYLINOSITOL 3-KINASE BY QUERCETIN AND ANALOGS

Phosphatidylinositol (Ptdlns) 3-kinase is an enzyme involved in cellular responses to growth factors. Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyrano-4-one), a naturally occuring bioflavinoid, was found to inhibit Ptdlns 3-kinase with an IC50 of 1.3 μg/ml (3.8 μM); inhibition appears to be directed towards the ATP binding site of the kinase. Analogs of quercetin were also investigated as Ptdlns 3-kinase inhibitors, with the most potent compounds exhibiting IC50's in the range of 1.7-8.4 μg/ml (5-19 μM). In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit Ptdlns 3-kinase significantly (IC50 > 30 μg/ml). These findings suggest that flavinoids may serve as potent inhibitors of Ptdlns 3-kinase. Furthermore, the enzyme is much more sensitive to substituents at the 3-position of the flavinoid ring than are other protein and Ptdlns kinases, suggesting that specific inhibitors of Ptdlns 3-kinase can be developed to explore the biological role of the enzyme in cellular proliferation and growth factor response. © 1992.