OSI-027

OSI-027 is an inhibitor of the catalytic site of mTOR and, as a result, inhibits both mTORC1 and mTORC2 (IC₅₀s = 22 and 65 nM, respectively).^1,2 It is selective for mTOR over phosphatidylinositol 3-kinase isoforms and DNA protein kinase.² OSI-027 prohibits proliferation, induces autophagy, and potentiates apoptosis in BCR-ABL transformed cells and other cancer cells at 10 µM.^1,3,4 OSI-027 is effective in vivo, blocking the phosphorylation of targets of mTORC1 and mTORC2 and suppressing tumor growth in several different human xenograft models.^2,5

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1. Carayol, N., Vakana, E., Sassano, A., et al. Critial roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc. Natl. Acad. Sci. USA 107(28), 12469-12474 (2010).

2. Falcon, B.L., Barr, S., Gokhale, P.C., et al. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res. 71(5), 1573-1583 (2011).

3. Gupta, M., Hendrickson, A.E.W., Yun, S.S., et al. Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces puma-dependent apoptosis in lymphoid malignancies. Blood 119(2), 476-487 (2012).

4. Vakana, E., Sassano, A., and Platanias, L.C. Induction of autophagy by dual mTORC1-mTORC2 inhibition in BCR-ABL-expressing leukemic cells. Autophagy 6(7), 966-967 (2010).

5. Bhagwat, S.V., Gokhale, P.C., Crew, A.P., et al. Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: Distinct from rapamycin. Mol. Cancer Ther. 10(8), 1394-1406 (2011).