Deforolimus(MK-8669)

• Catalog No.: S1022
• CAS Number: 572924-54-0
• M. F.: C53H84NO14P
• M. W.: 990.206121
• Storage: -20°C

SYNONYMS

• IUPAC name: (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^{4,9}]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate
• IUPAC Traditional name: ridaforolimus
• Synonyms: AP23573; MK-8669; Ridaforolimus

DATABASE IDS

• CAS Number: 572924-54-0

PROPERTIES

• Target: mTOR
• Salt Data: Free Base
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cancer

Biological Activity

• Description: Deforolimus (Ridaforolimus, AP23573, MK-8669) is a selective mTOR inhibitor with IC50 of 0.2 nM.
• Targets: mTOR
• IC50: 0.2 nM ^[1]
• 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 p70S6K^Thr389 in A549, H1703 and H157 cells, except H1666 that may express a resistant variant of mTORC1, and causes increased phosphorylation of pAKT^ser473 and pAKT^Thr308 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]

Combination Therapy

• Description: Deforolimus combined with Lapatinib results in synergistic inhibition of proliferation, reduces anchorage-independent growth, and reduces in vivo tumor growth of HER2-overexpressing breast cancer cells that have primary trastuzumab resistance. ^[3] Deforolimus in combination with Bicalutamide produces synergistic antiproliferative effects in prostate cancer cells in vitro, and exhibits potent antitumor activity with parallel reductions in plasma PSA levels in vivo. ^[4] Deforolimus in combination with MK-2206 is highly effective for inhibiting castration-resistant prostate cancer (CRPC) in preclinical studies in vivo using a refined genetically engineered mouse model of the disease. ^[5]

Protocol

• Protocol: 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).
• Protocol: 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
• Methods: Cells are seeded at 2-3 × 10^4/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.
• Protocol: 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
• Doses: ~10 mg/kg
• Administration: Intraperitoneally

References

• References: [1] Rivera VM, et al. Mol Cancer Ther, 2011, 10(6), 1059-1071.
• References: [2] Legrier ME, et al. Cancer Res, 2007, 67(23), 11300-11308.
• References: [3] Gayle SS, et al. Anticancer Agents Med Chem, 2012, 12(2), 151-162.
• References: [4] Squillace RM, et al. Int J Oncol, 2012, 41(2), 425-432.
• References: [5] Floc'h N, et al. Cancer Res, 2012, 72(17), 4483-4493.

REFERENCES

• Floc'h N, et al. Cancer Res, 2012, 72(17), 4483-4493.
• 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.
• Squillace RM, et al. Int J Oncol, 2012, 41(2), 425-432.