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.
|Source||Oncotarget (2015). Figure 2. OSI-027|
|Cell Lines||PDAC cell lines|
|Concentrations||5 and 10 μM|
|Incubation Time||48 and 72 h|
|Results||Flow cytometry assay showed 5 μM OSI-027 induced cell cycle arrest in the G0/G1 phase in Panc-1, BxPC-3, and CFPAC-1 cells, whereas RAPA had little effect on cell cycle. Moreover, 10 μM OSI-027 further upregulated the proportion of cells arrested in G0/ G1 phase|
|Cell lines||MDA-MB-231, MDA MB 435, PC-3, OVCAR-3, A549, DU145, NCI-H2122, U 87 MG and ACHN cell lines|
|Preparation method||For assays of cell proliferation, cells were seeded into 96-well plates and incubated for 3 days in the presence of OSI-027 or OXA-01 at various concentrations. Inhibition of cell growth was determined by luminescent quantification of intracellular ATP content using CellTiterGlo® (Promega). Proliferation on Day 0 vs. 72h was used to plot dose-response curves for IC50 calculations and to determine cell death.|
|Incubation time||72 h|
|Animal models||nu/nu CD-1 mice bearing MDA-MB-231 xenograft model|
|Dosages||25 or 65 mg/kg QD for 14 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies.
Gupta M, et al. Blood. 2012 Jan 12;119(2):476-87. PMID: 22080480.
Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin.
Bhagwat SV, et al. Mol Cancer Ther. 2011 Aug;10(8):1394-406. PMID: 21673091.
Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors.
Altman JK, et al. Clin Cancer Res. 2011 Jul 1;17(13):4378-88. PMID: 21415215.
Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors.
Falcon BL, et al. Cancer Res. 2011 Mar 1;71(5):1573-83. PMID: 21363918.
Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells.
Carayol N, et al. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12469-74. PMID: 20616057.
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