SC-31 * RATIONAL DESIGN OF A PI3-KINASE/mTOR INHIBITOR CYTOTOXIC TO BRAIN CANCER STEM CELLS UNDER HYPOXIA

Abstract

Small molecules that modulate cancer stem cell (CSC) fate and function offer therapeutic potential to improve patient outcome. Malignant gliomas are highly aggressive primary brain tumors with few treatment options and an invariably fatal outcome. High-throughput screening and structure-guided design identified a novel, dual phosphatidylinositol-3-kinase (PI3K)/mammaliam target of rapamycin (mTOR) inhibitor that potently induced apoptosis in glioma cells and glioma patient-derived CSCs. The compound, designated DT61, inhibited PI3K, mTORC1 and mTORC2 kinase activities at nanomolar concentrations in a dose-dependent manner. DT61 dramatically reduced the level of the PI3-K α and β isoforms and led to a reduction in the site-specific phosphorylation and activity of the pro-survival serine-threonine kinase Akt/Protein Kinase B (PKB). DT61 inhibition of PI3K activity prevented the inactivation of glycogen synthase kinase (GSK-3beta) to enhance site-specific phosphorylation and proteasomal degradation of the c-myc oncoprotein that drives gliomagenesis. The apoptotic effect of DT61 on CSCs was synergistically enhanced when combined with radiation treatment, a standard-of-care modality for glioma treatment. Taken together, the results demonstrate that DT61 is a novel, highly effective dual PI3K/mTOR inhibitor that is cytotoxic to brain CSC under normoxia and hypoxia with potential benefit for glioma patients.