Ridaforolimus (Deforolimus, MK-8669)

Names

[ Name ]:
Ridaforolimus (Deforolimus, MK-8669)

[Synonym ]:
(1R,2R,4S)-4-{(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,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] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl}-2-methoxycyclohexyl dimethylphosphinate
Phosphinic acid, P,P-dimethyl-, (1R,2R,4S)-2-methoxy-4-[(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,26R,27R,34aS)-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontin-3-yl]propyl]cyclohexyl ester
Deforolimus
Ridaforolimus

Biological Activity

[Description]:

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.

[Related Catalog]:

Research Areas >> Cancer

[Target]

mTOR

[In Vitro]

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].

[In Vivo]

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].

[Cell Assay]

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].

[Animal admin]

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].

[References]

[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.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Boiling Point ]:
996.2±75.0 °C at 760 mmHg

[ Melting Point ]:
95-98ºC

[ Molecular Formula ]:
C₅₃H₈₄NO₁₄P

[ Molecular Weight ]:
990.206

[ Flash Point ]:
556.3±37.1 °C

[ Exact Mass ]:
989.562927

[ PSA ]:
211.31000

[ LogP ]:
3.12

[ Vapour Pressure ]:
0.0±0.6 mmHg at 25°C

[ Index of Refraction ]:
1.539

[ Storage condition ]:
Hygroscopic, -20?C Freezer, Under Inert Atmosphere

Ridaforolimus (Deforolimus, MK-8669)

Names

Biological Activity

Chemical & Physical Properties

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds