Dual mTORC1/mTORC2 inhibitor
OSI-027 is a potent and selective inhibitor of mTORC1 and mTORC2 with IC50 values of 22nM and 65nM, respectively [1].
OSI-027 is developed as a potent anticancer agent through inhibiting mTORC1 and mTORC2. It shows more than 100-fold selectivity against mTOR over other PI3K-related kinases in biochemical assays. In cellular assays, OSI-027 inhibits the phosphorylation of mTORC1 and mTORC2 substrates including AKT, PRAS40 and S6K1, results in the blockade of downstream signaling. It shows equipotent cellular inhibition of both mTORC1 and mTORC2. It is demonstrated that OSI-027 is more potent in inhibiting cell proliferation and inducing cell death than rapamycin in a lot of tumor cell lines. Besides that, OSI-027 is also found to cause apoptosis via inducing sub-G1 fraction significantly. Furthermore, OSI-027 shows potent antitumor activity in MDA-MB-231 breast cancer xenograft model and human ovarian cancer xenograft models. The antitumor spectrum of OSI-027 is found to be quite broad including breast, colon, lung, prostate, lymphoma, and head and neck cancer [1].
参考文献:
[1] 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. Molecular cancer therapeutics, 2011, 10(8): 1394-1406.
Kinase experiment: | Assays of a panel of 40 other recombinant kinases including both protein and lipid kinases are performed at 100 mM ATP concentration by SelectScreen profiling service. A broad panel of kinases is tested at a single concentration of OSI-027 or OXA-01 (3 μM) to evaluate percent inhibition of each kinase or mutant variant, using the Ambit KinomeScan platform[1]. |
Cell experiment: | To study the effect of drug treatment on cellular signaling, Ovcar-3 cells are plated in normal growth medium. After 24 hours, serum is removed and cells are serum-starved overnight. Rapamycin, OSI-027 and OXA-01 are solubilized in DMSO and added to cells at varying concentrations. After a two-hour incubation cells are growth factor stimulated with 10 ng/mL Insulin for 3 to 5 minutes, then rinsed with cold PBS and lysed[1]. |
Animal experiment: | Mice[1]For xenograft models, cells are harvested, implanted s.c. in the right flank of nu/nu CD-1 mice and tumor growth is analyzed. Mice bearing GEO xenografts are treated for 12 days with OSI-027 (65mg/kg) or vehicle and tumors collected at 2, 8, and 24 hours. Tumor growth inhibition and regression calculations are included. Rats[2]Specific pathogen-free female Lewis rats, male BN rats, male Lew-Tg(CAG-EGFP)YsRrrc rats and male Lew-TgYsRrrc rats are used. Orthotopic LT is undertaken. No antibiotics were used. Freshly prepared splenocytes (4×108, suspended in 500 μL PBS) of Lew-Tg YsRrrc rats are infused into each recipient via the dorsal penile vein immediately after LT (within 30 min). LTx-aGVHD model rats are divided into three experimental groups: RAPA (1 mg/kg), OSI-027 (1 mg/kg) or control (equal quantity of vehicle) groups; treatments are administered via the vena caudalis from day 7 to day 15. |
参考文献: [1]. Falcon BL, et al. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res. 2011 Mar 1;71(5):1573-83. | |
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