Home PI3K/Akt/mTOR mTOR inhibitor - FKBP inhibitor Ridaforolimus (Deforolimus, MK-8669)

Ridaforolimus (Deforolimus, MK-8669)

Catalog No.S1022 Synonyms: AP23573

For research use only.

Ridaforolimus (Deforolimus, MK-8669, AP23573) 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.

Ridaforolimus (Deforolimus, MK-8669) Chemical Structure

CAS No. 572924-54-0

Selleck's Ridaforolimus (Deforolimus, MK-8669) has been cited by 15 publications

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Biological Activity

Description Ridaforolimus (Deforolimus, MK-8669, AP23573) 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
FKBP12 [6] mTOR [1]
(HT-1080 cells)
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]

Protocol (from 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 Research:

[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 Research:

[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
  • Dosages: ~10 mg/kg
  • Administration: Intraperitoneally

Solubility (25°C)

In vitro

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
5% DMSO+40% PEG 300+5% Tween 80+50% H2O
For best results, use promptly after mixing.

 10mg/mL

Chemical Information

Molecular Weight 990.21
Formula

C53H84NO14P
CAS No. 572924-54-0
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)OP(=O)(C)C)C)C)O)OC)C)C)C)OC

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01431547 Completed Drug: dalotuzumab|Drug: ridaforolimus Solid Tumors Merck Sharp & Dohme Corp. February 2012 Phase 1
NCT01431534 Terminated Drug: Ridaforolimus Solid Tumors Merck Sharp & Dohme Corp. January 30 2012 Phase 1
NCT01380184 Completed Drug: ridaforolimus Cancer Advanced Merck Sharp & Dohme Corp. July 5 2011 Phase 1
NCT01295632 Completed Drug: ridaforolimus|Drug: MK-0752|Drug: MK-2206 Advanced Cancer Merck Sharp & Dohme Corp. February 2011 Phase 1
NCT01212627 Terminated Drug: Ridaforolimus Non-Small Cell Lung Cancer Angela Taber MD|Rhode Island Hospital|The Miriam Hospital|Memorial Hospital of Rhode Island|Roger Williams Medical Center|Brown University September 2010 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

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