Ridaforolimus (Deforolimus, MK-8669)

Catalog No.S1022

Ridaforolimus (Deforolimus, MK-8669) is a selective mTOR inhibitor with IC50 of 0.2 nM in HT-1080 cell line; while not classified as a prodrug, mTOR inhibition and FKBP12 binding is similar to rapamycin. Phase 3.

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Ridaforolimus (Deforolimus, MK-8669) Chemical Structure

Ridaforolimus (Deforolimus, MK-8669) Chemical Structure
Molecular Weight: 990.21

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Ridaforolimus (Deforolimus, MK-8669) is available in the following compound libraries:

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Product Information

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  • Research Area
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    Combination Therapy

Product Description

Biological Activity

Description Ridaforolimus (Deforolimus, MK-8669) is a selective mTOR inhibitor with IC50 of 0.2 nM in HT-1080 cell line; while not classified as a prodrug, mTOR inhibition and FKBP12 binding is similar to rapamycin. Phase 3.
Targets mTOR [1]
(HT-1080 cells)
IC50 0.2 nM
In vitro 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 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]
Features

Protocol(Only for Reference)

Kinase Assay: [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).

Cell Assay: [2]

Cell lines Colo205, H1755, H1395, H1666, A549, H157, and H1703 cells
Concentrations Dissolved in ethanol, final concentrations ~ 1 μM
Incubation Time 72-120 hours
Method 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.

Animal Study: [1]

Animal Models 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
Formulation Dissolved in ethanol, and diluted in a vehicle of 4% ethanol, 5% Tween 80, and 5% propylene glycol
Dosages ~10 mg/kg
Administration Intraperitoneally

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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

References

[1] Rivera VM, et al. Mol Cancer Ther, 2011, 10(6), 1059-1071.

[2] Legrier ME, et al. Cancer Res, 2007, 67(23), 11300-11308.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02828917 Not yet recruiting de Novo or Restenosis Lesions Medinol Ltd. September 2016 Phase 3
NCT02834806 Not yet recruiting Stenosis Medinol Ltd. August 2016 --
NCT02736344 Recruiting Heart Disease Medinol Ltd. April 2016 Phase 3
NCT01605396 Active, not recruiting Breast Neoplasms Merck Sharp & Dohme Corp. July 2012 Phase 2
NCT01431547 Completed Solid Tumors Merck Sharp & Dohme Corp. February 2012 Phase 1

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Chemical Information

Download Ridaforolimus (Deforolimus, MK-8669) SDF
Molecular Weight (MW) 990.21
Formula

C53H84NO14P

CAS No. 572924-54-0
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms AP23573
Solubility (25°C) * In vitro DMSO 198 mg/mL (199.95 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
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.
Chemical Name 42-​(dimethylphosphinate​)-rapamycin

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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