Abstract
The serine/threonine kinase AKT/PKB has a critical role in the regulation of cell proliferation. Because AKT signaling is deregulated in numerous human malignancies, it has become an attractive anticancer drug target. A number of small molecule AKT kinase inhibitors have been developed; however, severe side effects have prevented their use in clinical trials. To find inhibitors of AKT1 signaling with principally novel mechanism of action, we carried out a live cell-based screen for small molecule inhibitors of physical interaction between AKT1 and its primary activator PDPK1. The screen revealed one molecule-NSC156529, which downregulated AKT1 signaling, efficiently decreased the proliferation of human cancer cells in vitro, and substantially inhibited the growth of prostate tumor xenografts in vivo. Interestingly, the treated tumor xenografts exhibited higher expression level of normal prostate differentiation markers but did not show augmented cell death, suggesting that the identified compound primarily enhances the differentiation of malignant cells toward normal prostate epithelium and thus poses as an attractive lead compound for developing novel antitumor agents with less cytotoxic side effects.
Highlights
The serine/threonine kinase AKT belongs to the AGC family of kinases and has a central role in regulating the survival and proliferation of normal and malignant cells [1, 2]
Screening for the inhibitors of AKT1 and PDPK1 interaction To identify the inhibitors of AKT1 and PDPK1 interaction, we carried out a small chemical library screen using the NCI Diversity Set I small molecular compound library consisting of 2,000 compounds in live cells
To rule out unspecific modulation of the luciferase readouts, quadruple replicates of H1299 cells transfected with pCNEO cloning vector; H1299 cells transfected with p53-F1 and HDM2-F2 treated with either DMSO or Nutlin-3; and H1299 cells transfected with AKT1-F1, PDPK1-F2 treated with DMSO were used (Supplementary Table S4)
Summary
The serine/threonine kinase AKT ( known as protein kinase B, PKB) belongs to the AGC family of kinases and has a central role in regulating the survival and proliferation of normal and malignant cells [1, 2]. A variety of AKT inhibitors have been developed to date [9]. Most of these are the inhibitors of kinase activity and by binding to its kinase active site act as ATP competitors. Because the ATP binding pocket of AKT/PKB, PKA, and PKC is highly homologous, these inhibitors have an activity toward PKA and PKC [10]. Phosphatidylinositol (PI) analogues block PI [3,4,5]P3 binding to AKT, prevent its translocation to plasma membrane and subsequent activation [11]. A few inhibitors of PDPK1, the critical upstream activator of AKT, have been developed, which
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