Ridaforolimus (Deforolimus, MK-8669)
Catalog No.S1022 Synonyms: AP23573
Molecular Weight(MW): 990.21
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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|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.|
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. 
|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. |
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).
-  Rivera VM, et al. Mol Cancer Ther, 2011, 10(6), 1059-1071.
-  Legrier ME, et al. Cancer Res, 2007, 67(23), 11300-11308.
-  Gayle SS, et al. Anticancer Agents Med Chem, 2012, 12(2), 151-162.
|In vitro||DMSO||198 mg/mL (199.95 mM)|
|In vivo||30% PEG400+0.5% Tween80+5% propylene glycol||20 mg/mL|
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Clinical Trial Information
|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|
|NCT01431534||Active, not recruiting||Solid Tumors||Merck Sharp & Dohme Corp.||January 2012||Phase 1|
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