Regulating the activity of Akt by inhibiting the pleckstrin homology domain‐PtdIns(3,4,5)P3 interaction using flavonoids

Abstract

Since over‐activation of cellular signalling was frequently observed from a wide range of cancer types, the down‐regulation of signalling is regarded as a goal for drug development. A serine‐threonine kinase, AKT, playing a pivotal role in tumour progression was also over‐activated in cancer cells; thereby AKT was believed as a critical therapeutic target for cancer intervention. In this study, we targeted the pleckstrin homology (PH) domain to down‐regulate AKT activity via inhibiting phosphatidylinositol‐3,4,5‐triphosphate (PIP3) binding using by small natural molecules, flavonoids. The inhibition rates of flavonoids were evaluated by liposome pull‐down assay coupled with fluorescence spectrophotometry, and several flavonoids including 3,6‐dihydroxyflavone and 6,2′‐dihydroxyflavone showed about 40 and 50 % of inhibition at 10μM. Moreover, it was confirmed that flavonoids targeting PH domain‐PIP3 interaction decreased the activity of AKT in cellular levels. And then, we further analyzed the relationship between structure and activity using QSAR to find optimum structural moiety because of the structural similarity of flavonoids. Although it needed more study to derive optimum moiety of flavonoids as anticancer drugs for targeting AKT, we believed that this finding would provide a strong evidence to regulate AKT activity by targeting the regulatory domain instead of catalytic kinase domain.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.