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

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Ridaforolimus (Deforolimus, MK-8669) mTOR inhibitor

Cat.No.S1022

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) mTOR inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 990.21

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Quality Control

Batch: Purity: >97%
97

Solubility

In vitro
Batch:

DMSO : 100 mg/mL (100.98 mM)
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Water : Insoluble

Ethanol : Insoluble

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Chemical Information, Storage & Stability

Molecular Weight 990.21 Formula

C53H84NO14P

 Storage (From the date of receipt)
CAS No. 572924-54-0 Download SDF Storage of Stock Solutions

Synonyms AP23573 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

Mechanism of Action

Targets/IC50/Ki
FKBP12
mTOR
(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. 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.

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).
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.

References
  • [4] https://pubmed.ncbi.nlm.nih.gov/22614157/
  • [5] https://pubmed.ncbi.nlm.nih.gov/22815528/
  • [6] https://pubmed.ncbi.nlm.nih.gov/19383975/

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

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

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