Ridaforolimus (Deforolimus, MK-8669)

Ridaforolimus (Deforolimus, MK-8669)は一種の選択性的なmTOR抑制剤で、HT-1080細胞の中でIC50値は0.2 nMです。Ridaforolimus (Deforolimus, MK-8669)はプロドラッグとして分類されません。mTOR抑制とFKBP12結合はラパマイシン( rapamycin)に似っています。臨床3期。

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Ridaforolimus (Deforolimus, MK-8669) 化学構造
分子量: 990.21

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製品説明

  • Compare mTOR Inhibitors
    mTOR製品生物活性の比較
  • 研究分野
  • Combination Therapy
    併用療法

製品の説明

生物活性

製品説明 Ridaforolimus (Deforolimus, MK-8669)は一種の選択性的なmTOR抑制剤で、HT-1080細胞の中でIC50値は0.2 nMです。Ridaforolimus (Deforolimus, MK-8669)はプロドラッグとして分類されません。mTOR抑制とFKBP12結合はラパマイシン( rapamycin)に似っています。臨床3期。
ターゲット mTOR
IC50 0.2 nM [1]
In vitro試験 Treatment of HT-1080 cells with Deforolimus induces a dose-dependent inhibition of phosphorylation of both S6 and 4E-BP1, with IC50 of 0.2 nM and 5.6 nM, respectively, and leads to a decrease in cell size, an increase in the proportion of cells in the G1 phase of the cell cycle, and inhibition of glucose uptake. Deforolimus displays significant antiproliferative activity a broad panel of cell lines with EC50 of 0.2-2.3 nM. Deforolimus potently and selectively inhibits VEGF production in a dose-dependent manner. [1] Deforolimus treatment significantly induces growth suppression in human NSCLC cell lines with IC30 values of 2.45-8.83 nM, with the exception of H157 with IC30 of >20 nM. Deforolimus treatment (2.8-5.9 nM) significantly dephosphorylates p70S6KThr389 in A549, H1703 and H157 cells, except H1666 that may express a resistant variant of mTORC1, and causes increased phosphorylation of pAKTser473 and pAKTThr308 in A549 and H1703 cells. Deforolimus in combination with the MEK inhibitors, CI-1040 or PD0325901 exhibits dose-dependent synergism in lung cancer cell lines, which is associated with the suppression of proliferation rather than enhancement of cell death, involving the inhibition of ribosomal biogenesis by 40% within 24 hours and a decreased polysome/monosome ratio. [2]
In vivo試験 Administration of Deforolimus exerts significant antitumor effects in mice bearing PC-3 (prostate), HCT-116 (colon), MCF7 (breast), PANC-1 (pancreas) or A549 (lung) xenografts in a dose-dependent manner, and inhibits mTOR signaling in in SK-LMS-1 xenograft model associated with inhibition of tumor growth. [1]
臨床試験
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Cell based target inhibition HT-1080 cells are treated with increasing concentrations of Deforolimus (0-100 nM) for 2 hours, prior to harvest. Cellular lysates are extracted in denaturing lysis buffer, resolved on SDS-PAGE and transferred to PVDF membranes. After blocking, membranes are incubated with primary antibodies for 1 hour, followed by appropriate HRPconjugated secondary antibodies for 1 hour at room temperature. Immunoreactive proteins are detected using enhanced chemiluminescence and autoradiography performed by exposure to X-ray film. IC50 is determined from the inhibition of levels of phosphorylated ribosomal protein S6 (p-S6) and 4E-BP1 (p-4E-BP1).

細胞アッセイ: [2]

細胞株 Colo205, H1755, H1395, H1666, A549, H157, and H1703 cells
濃度 Dissolved in ethanol, final concentrations ~ 1 μM
反応時間 72-120 hours
実験の流れ Cells are seeded at 2-3 × 104/mL, and serial dilutions of Deforolimus are added after 2 hours, for at least three cell doublings (72-120 hours). Deforolimus effects are measured using the CellTiter 96 Aqueous nonradioactive cell proliferation assay and Sulforhodamine B assays. For Deforolimus, growth effects are described as IC30 because rapamycin and its derivatives do not significantly impede cell proliferation.

動物実験: [1]

動物モデル Male and female athymic NCr-nu mice with xenografts established by subcutaneous implantation of PC-3, A549, HCT-116, MCF7, PANC-1 and SK-LMS-1 tumors
製剤 Dissolved in ethanol, and diluted in a vehicle of 4% ethanol, 5% Tween 80, and 5% propylene glycol
投薬量 ~10 mg/kg
投与方法 Intraperitoneally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Ridaforolimus (Deforolimus, MK-8669) SDF
分子量 990.21
化学式

C53H84NO14P

CAS No. 572924-54-0
保管 3年-20℃
2年-80℃in solvent
別名 AP23573
溶解度 (25°C) * In vitro DMSO 198 mg/mL (199.95 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 20 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 42-​(dimethylphosphinate​)-rapamycin

文献中の引用 (4)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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