Home PI3K/Akt/mTOR mTOR inhibitor - FKBP inhibitor Ridaforolimus (Deforolimus, MK-8669) For research use only.

Ridaforolimus (Deforolimus, MK-8669)

Synonyms: AP23573

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

Ridaforolimus (Deforolimus, MK-8669) Chemical Structure

CAS No. 572924-54-0

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Ridaforolimus (Deforolimus, MK-8669) Related Products

Signaling Pathway

mTOR Signaling Pathways

mTOR Signaling Pathway

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
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]
Kinase Assay 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 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.
In Vivo
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]
Animal Research 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
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01431547 Completed
Solid Tumors
Merck Sharp & Dohme LLC
 February 2012 Phase 1
NCT01431534 Terminated
Solid Tumors
Merck Sharp & Dohme LLC
 January 30 2012 Phase 1
NCT01380184 Completed
Cancer Advanced
Merck Sharp & Dohme LLC
 July 5 2011 Phase 1
NCT01295632 Completed
Advanced Cancer
Merck Sharp & Dohme LLC
 February 2011 Phase 1
NCT01212627 Terminated
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

Chemical Information & Solubility

Molecular Weight 990.21 Formula

C53H84NO14P
CAS No. 572924-54-0 SDF Download Ridaforolimus (Deforolimus, MK-8669) SDF
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
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 100 mg/mL ( (100.98 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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