Deforolimusis (also known as Ridaforolimus, AP23573 and MK-8669) is an investigational targeted and small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT and PTEN known to be important to malignancy. Deforolimusis blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis.
|Cell lines||HCT-116, SK-UT-1, HT-1080, SW872, MCF-7, PC-3 cell lines|
|Preparation method||In vitro proliferation assays. Exponentially growing cell lines were plated into two 96-well plates and incubated overnight at 37°C. Twenty-four hours after plating, 1 plate (D1) was aspirated and stored at −80°C. The other plate (D4) was treated with 10-fold serial dilutions of ridaforolimus (1,000 to 0.0001 nmol/L) or vehicle (ethanol). Following 72 hours culture at 37°C, the plates were aspirated and stored at −80°C for proliferation analysis. The D1 and D4 plates were assessed simultaneously for cell growth using the CyQUANT Cell Proliferation Assay Kit (Invitrogen). Doubling time (DT) = [0.301 × (72)/log(day4/day1)]. Doublings = 72/DT. Cell growth rate (%) = doublings ridaforolimus/doublings vehicle × 100. Imax = 100 − cell growth rate (%) at the dose at which maximum inhibition is observed. Imax was used to determine the relative sensitivity of each cell line.|
|Concentrations||0~1000 n M|
|Incubation time||72 h|
|Animal models||mice bearing PC-3, A549, HCT-116, MCF7, and PANC-1 tumors xenograft model|
|Formulation||diluted in a vehicle of 4% ethanol, 5% Tween 80, and 5% propylene glycol|
|Dosages||3 and 10 mg/kg (a) daily, 5 continuous days every other week and (b) once weekly|
|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.
Treating metastatic soft-tissue or bone sarcomas - potential role of ridaforolimus.
Keedy VL. Onco Targets Ther. 2012;5:153-60. PMID: 22942649.
A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer.
Lush et al. Cancer Chemother Pharmacol. 2012 Aug 10. PMID: 22878520.
Safety and Preliminary Efficacy Analysis of the mTOR Inhibitor Ridaforolimus in Patients With Taxane-Treated, Castration-Resistant Prostate Cancer.
Amato et al. Clin Genitourin Cancer. 2012 Jun 11. PMID: 22695254.
Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models.
Squillace et al. Int J Oncol. 2012 Aug;41(2):425-32. PMID: 22614157.
The effect of multiple doses of rifampin and ketoconazole on the single-dose pharmacokinetics of ridaforolimus.
Stroh et al. Cancer Chemother Pharmacol. 2012 May;69(5):1247-53. PMID: 22290273.
Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial.
Berk et al. Cancer Chemother Pharmacol. 2012 May;69(5):1369-77. PMID: 22231376.
Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens.
Rivera VM, et al. Mol Cancer Ther. 2011 Jun;10(6):1059-71. PMID: 21482695.
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Temsirolimus (CCI-779) is a specific mTOR inhibitor with IC50 of 1.76 μM.
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