ATPS-94THIRD GENERATION mTOR INHIBITORS IN GLIOBLASTOMA

Abstract

The mTOR serine-theronine kinase exists in two distinct multi-protein mTORC complexes. First generation allosteric inhibitors of mTOR (rapalogs) block mTORC1, whereas second generation mTOR kinase inhibitors (MLN128) inhibit both mTORC1 and mTORC2. Although rapalogs and mTOR kinase inhibitors are in clinical trials, rapalogs are inefficient mTORC1 blockers, while blockade of mTORC2 by mTORCi is poorly tolerated by normal cells, perhaps due to components of mTORC2 being essential genes. We synthesized and here characterize third generation mTOR kinase inhibitors that show improved efficacy in glioblastoma, tied to highly efficient blockade of mTORC1, with relative mTORC2 sparing. Compared to rapamycin, MLN128, and the AKT inhibitor MK-2206, third generation mTOR inhibitors were 10-100 fold more active as antiprolfierative agents, driving arrest in G1 without appreciable induction of apoptosis. Third generation mTOR inhibitors demonstrated efficacy in cells wild-type and mutant for PTEN, a negative regulator of PI3K signaling. We demonstrate that third generation efficiently blocked the mTORC1 targets S6K and EIF4E, and traced the increased activity of these agents mTOR inhibitors to higher affinity for mTORC1, in comparison with rapamycin and MLN128. We also demonstrated that third generation mTOR inhibitors cross the blood brain barrier. In vivo testing in orthotopic PDX models is underway, and will be discussed.