Ras and PI-3K pathways are activated in most human cancers and converge on mTOR to stimulate tumor cell growth and metastasis. The cytoplasmic protein kinase mTOR has emerged as a critical regulator of tumor cell growth control. Two distinct mTOR complexes known as mTORC1 (Raptor- mTOR complex) and mTORC2 (Rictor-mTOR complex) have been identified. mTORC1 phosphorylates 4E-BP1 to regulate cap-dependent translation of genes critical for tumor growth (e.g. Cyclin D1, HIF1a). Potent, selective inhibitors of the mTOR kinase domain, which inhibit both mTORC1 and mTORC2, are expected to inhibit growth of epithelial and mesenchymal-like tumor cells, with anti-proliferative and pro-apoptotic consequences in both rapamycin-sensitive and rapamycin-insensitive cell lines. Further, dual TORC1/TORC2 inhibitors are expected to be effective against a broad range of tumor types and to potentiate the antitumor activity of other MTT’s such as the EGFR tyrosine kinase inhibitor erlotinib. A novel small molecule dual TORC1/TORC2 kinase inhibitor (OSI-027) was discovered and developed at OSI. OSI expects to initiate a clinical trial program for OSI-027 in the first half of 2008.

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