Ridaforolimus (Deforolimus, MK-8669)

Deforolimus (AP23573; MK-8669) is a potent and selective mTOR inhibitor; inhibits ribosomal protein S6 phosphorylation with an IC50 of 0.2 nM in HT-1080 cells.

Research Areas >> Cancer

mTOR

Treatment of HT-1080 fibrosarcoma cells with deforolimus results in a dose-dependent inhibition of phosphorylation of both S6 and 4E-BP1, with IC50s of 0.2 and 5.6 nM, respectively, and EC50s of 0.2 and 1.0 nM, respectively. In HT-1080 cells, the EC50 for inhibition of cell proliferation (0.5 nM) is similar to the EC50s for inhibition of S6 and 4E-BP1 phosphorylation. Exposure to deforolimus reduces the proliferation of cell lines representing a variety of tumor types. Administration of deforolimus to tumor cells in vitro elicit dose-dependent inhibition of mTOR activity with concomitant effects on cell growth and division. Deforolimus exhibits a predominantly cytostatic mode of action, consistent with the findings for other mTOR inhibitors. Potent inhibitory effects on vascular endothelial growth factor secretion, endothelial cell growth, and glucose metabolism[1].

Deforolimus inhibits tumor growth in mice bearing PC-3 (prostate), HCT-116 (colon), MCF7 (breast), PANC-1 (pancreas), or A549 (lung) xenografts. Deforolimus inhibits tumor growth in a dose-dependent manner, with 0.3 mg/kg being the lowest dose that inhibits tumor growth significantly and 3 and 10 mg/kg doses achieving maximum inhibition[1].

Cells are treated with 10-fold serial dilutions of deforolimus (1,000 to 0.0001 nM) or vehicle (ethanol). Following 72 hours culture at 37°C, the plates are aspirated and stored at −80°C for proliferation analysis[1].

Mice: Animals selected with tumors in the proper size range are assigned to various treatment groups. Deforolimus, at dosages of 3 and 10 mg/kg, is administered i.p. on 2 different treatment schedules: (a) daily, 5 continuous days every other week and (b) once weekly. The control group is untreated[1].

[1]. Rivera VM, et al. Deforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther. 2011 Jun;10(6):1059-71.

[2]. Brandt M, et al. mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis. Cell Metab. 2018 Jan 9;27(1):118-135.e8.

Rapamycin (Sirolimus) | Torin 1 | MHY1485 | Sapanisertib (MLN0128) | AZD8055 | Dactolisib (BEZ235) | Vistusertib (AZD2014) | Torkinib (PP242) | LY3023414 | Torin 2 | GSK2126458(GSK458) | PF-04691502 | Salidroside | PQR-309 | OSI-027