OSI-027

OSI-027 is a potent, orally bioavailable mammalian target of rapamycin (mTOR) kinase inhibitor with potential antineoplastic activity. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Kα, PI3Kβ, PI3Kγ and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 potently inhibits proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling. In contrast to rapamycin, OSI-027 induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Furthermore, OSI-027 shows superior efficacy compared with rapamycin in COLO 205 and GEO colon cancer xenograft models. OSI-027 is currently in phase I clinical trials in cancer patients.