Description
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.
Mechanism of action
Ridaforolimus (also known as AP23573 and MK-8669; formerly known as deforolimus) is an investigational targeted and small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT and PTEN known to be important to malignancy. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis.
Description
MK-8669 is a rapamycin analog that selectively inhibits mTOR (IC
50 = 0.2 nM). Like rapamycin, MK-8669 binds FKBP12 to form a complex that associates with the FKBP-rapamycin binding domain on mTOR and allosterically inhibits mTORC1 kinase activity. MK-8669 is more water soluble than rapamycin and is amenable to oral or intravenous administration. Formulations containing rapalogs, including MK-8669, have promise against a subset of cancers, including advanced kidney cancer. MK-8669 is also being examined for effectiveness against cancers when used in combination with other chemotherapeutic compounds.
Chemical Properties
Off-White Solid
Uses
An immunosupressant and is currently being investigated for use in cancer treatments. Ridaforolimus may act as a regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival. Ridaforolimus, was formerly known as Deforolimus. Potent mTORC1 inhibitor.
Uses
Ridaforolimus is a semisynthetic macrocyclic lactone prepared from rapamycin by selective alkylation of the 42-hydroxy group with a dimethylphosphinate moiety. Like all tacrolimus analogues, ridaforolimus binds to receptor protein, FKBP12. The complex then binds to mTOR preventing its interaction with target proteins. Ridaforolimus is extensively cited in the literature with over 70 citations.
Definition
ChEBI: A semisynthetic derivative that is sirolimus in which hydroxy group attached to the cyclohexyl moiety has been converted to the corresponding dimethylphosphinate.
in vivo
mice bearing mcf7 (breast), pc-3 (prostate), a549 (lung), hct-116 (colon) or panc-1 (pancreas) xenografts have revealed the antitumor efficacy of ridaforolimus [1].
References
[1] rivera vm1, squillace rm, miller d, berk l, wardwell sd, ning y, pollock r, narasimhan ni, iuliucci jd, wang f, clackson t.ridaforolimus (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.
