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  • CC-115 hydrochloride
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    CC-115 hydrochloride

    A dual inhibitor of mTOR and DNA-PK

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    CC-115 hydrochloride的二维码
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    • 5mg
      ¥987.00
      790.00
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    • 10mg
      ¥1625.00
      1300.00
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    • 50mg
      ¥5612.00
      4490.00
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    • 100mg
      ¥10600.00
      8480.00
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    • 货号: ajce52484
    • CAS: 1300118-55-1
    • 别名:
    • 分子式: C16H17ClN8O
    • 分子量: 372.81
    • 纯度: >98%
    • 溶解度: DMSO : ≥ 30 mg/mL (80.47 mM)
    • 储存: Store at -20°C
    • 库存: 现货

    Background

    CC-115 is a dual inhibitor of mammalian target of rapamycin (mTOR) and DNA protein kinase (DNA-PK; IC50s = 0.021 and 0.013 ?M, respectively).1,2 It is selective for mTOR and DNA-PK over PI3Kα, ATM, and ATR (IC50s = 0.85, >30, and >30 ?M, respectively). CC-115 inhibits growth in a panel of 123 cancer cell lines, including breast, head and neck, and lung cancer cells (GI50s = 0.015-1.77 ?M), and non-homologous end joining (NHEJ) in CAL-51 and MDA-MB-231 breast, PC3 prostate, and HCT116 colon cancer cells (IC50s = 3.15, 2.16, 2.72, and 6.35 ?M, respectively).2 It reduces tumor growth in a PC3 prostate cancer mouse xenograft model when administered at doses of 0.25, 0.5, and 1 mg/kg twice per day.1


    1.Mortensen, D.S., Perrin-Ninkovic, S.M., Shevlin, G., et al.Optimization of a series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors and the discovery of CC-115J. Med. Chem.58(14)5599-5608(2015) 2.Tsuji, T., Sapinoso, L.M., Tran, T., et al.CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitroOncotarget8(43)74688-74702(2017)

    Protocol

    Kinase experiment:

    An HTR-FRET substrate phosphorylation assay is employed for mTOR kinase. PI3Kα IC50 determinations are outsourced using the mobility shift assay format. Compounds (e.g., CC-115) are assessed against concentrations of ATP at approximately the Km for the assay, with average ATP Km of 15 μM and 50 μM for the mTOR and PI3K assays, respectively[1].

    Cell experiment:

    PC-3 cells are cultured in growth media. For biomarker studies cells are treated for 1 h and then assayed for pS6 and pAkt levels using MesoScale technology. For proliferation experiments, cells are treated with compound (e.g., CC-115) and then allowed to grow for 72 h. All data are normalized and represented as a percentage of the DMSO-treated cells. Results are then expressed as IC50 values[1].

    Animal experiment:

    Mice[1]Encouraged by the observed exposures, CC-115 is advanced into single dose PK/PD studies assessing mTOR pathway biomarker inhibition in tumor bearing mice. PC-3 tumor-bearing mice are administered with a single dose of CC-115, dosed orally at either 1 or 10 mg/kg, and plasma and tumor samples are collected at various time points for analysis. Significant inhibition of both mTORC1 (pS6) and mTORC2 (pAktS473) is observed for all compounds and the level of biomarker inhibition correlated to plasma compound levels.

    参考文献:

    [1]. Mortensen DS, et al. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-5608.

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