The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs.
Phosphatidylinositol (PtdIns) 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 PtdIns 3-kinase with an IC50 of 1.3 micrograms/ml (3.8 microM); inhibition appears to be directed towards the ATP binding site of the kinase. Analogs of quercetin were also investigated as PtdIns 3-kinase inhibitors, with the most potent compounds exhibiting IC50's in the range of 1.7-8.4 micrograms/ml (5-19 microM). In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit PtdIns 3-kinase significantly (IC50 greater than 30 micrograms/ml). These findings suggest that flavinoids may serve as potent inhibitors of PtdIns 3-kinase. Furthermore, the enzyme is much more sensitive to substituents at the 3-position of the flavinoid ring than are other protein and PtdIns kinases, suggesting that specific inhibitors of PtdIns 3-kinase can be developed to explore the biological role of the enzyme in cellular proliferation and growth factor response.
Matter
W F
WF
Lilly Research Laboratories, Indianapolis IN 46285-0403.
Brown
R F
RF
Vlahos
C J
CJ
D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D005419:Flavonoids / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D005419:Flavonoids; D011794:Quercetin; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases