The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates cell growth, metabolism, proliferation and survival by integrating growth factor signaling with cellular nutritional status and energy use.  The PI3K/Akt pathway is frequently mutated in many cancers, leading to hyperactivation of mTOR signaling,making mTOR an attractive drug target.  Rapamycin analogs such as temsirolimus and everolimus, which target only the mTORC1 complex, have shown some clinical activity. It is hypothesized that mTOR kinase inhibitors, blocking both mTORC1 and mTORC2 signaling, should have expanded therapeutic potential.  We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model.  A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series.  Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Ka lipid kinase.  Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.

Use of core modification to identify a new series of mTOR kinase inhibitors and CC214-2, an orally available, selective inhibitor of mTOR kinase

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.