Deforolimus (AP23573, MK-8669)

Deforolimus (AP23573, MK-8669) - Names and Identifiers

Name	(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,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[30.3.1.04,
Synonyms	Deforolimus Ridaforolimus Deforolimus (AP23573) RIDAFOROLIMUS DEFOROLIMUS DeforoliMus (RidaforoliMus) Deforolimus (AP23573, MK-8669) 42-(Dimethylphosphinate)rapamycin Ridaforolimus (Deforolimus, MK-8669) DeforoliMus(AP 23573,MK-8669,RidaforoliMus) (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,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[30.3.1.04,
CAS	572924-54-0

Deforolimus (AP23573, MK-8669) - Physico-chemical Properties

Molecular Formula	C53H84NO14P
Molar Mass	990.21
Density	1.18±0.1 g/cm3(Predicted)
Melting Point	95-98°C
Boling Point	996.2±75.0 °C(Predicted)
Solubility	DMSO:20 mg/ml solution is unstable. It is recommended that you use it now and use it immediately.
Appearance	Solid
Color	Off-White to Pale Yellow
pKa	10.40±0.70(Predicted)
Storage Condition	Hygroscopic, -20°C Freezer, Under Inert Atmosphere
Stability	Hygroscopic
Use	Ridaforolimus, also known as AP23573, is an investigational small-molecule inhibitor of mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival. mTOR integrates 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. It has had promising results in a clinical trial for advanced soft tissue and bone sarcoma.
In vitro study	Deforolimus treatment of HT-1080 cells inhibited the phosphorylation of S6 and 4E-BP1 in a dose-dependent manner, with IC50 of 0.2 nM and 5.6 nM, EC50 of 0.2 nM and 1.0 nM, respectively, it also leads to a decrease in cell size, an increase in G1 phase cells, and an inhibition of glucose uptake with an EC50 of 0.1-1 nM. Deforolimus acts on a panel of cell lines and has significant anti-proliferative activity with an EC50 of 0.2-2.3 nM. Deforolimus potently and selectively inhibits VEGF production in a dose-dependent manner with an EC50 of ~ 0.1 nM. Deforolimus significantly inhibited cell growth in human NSCLC cell lines (except H157 cells) with IC30 of 2.45-8.83 nM, while in H157 cells, IC30 >20 nM. 2.8-5.9 nM Deforolimus treated A549, H1703 and H157 cells (except H1666 expressing mTORC1 resistance mutation) dephosphorylated p70S6KThr389 and acted on A549 and H1703 cells, increased phosphorylation of pAKTser473 and pAKTThr308. The combination of Deforolimus and MEK inhibitor CI-1040 or PD0325901 in human lung cancer cell lines has a synergistic effect, which is dose-dependent and is associated with inhibition of cell proliferation rather than increased cell death, after 24 hours of treatment, inhibits ribosome synthesis by 40% and decreases the Polysome/chromatid ratio.
In vivo study	Deforolimus treatment of mice bearing PC-3 (prostate), HCT-116 (colon), MCF7 (thymus), PANC-1 (pancreas) or A549 (lung) xenografts with significant anticancer effects, this effect is dose-dependent, and it acts on SK-LMS-1 transplanted tumors and inhibits mTOR signaling.

Deforolimus (AP23573, MK-8669) - Reference

Reference

1: Blay JY. Updating progress in sarcoma therapy with mTOR inhibitors. Ann Oncol. 2010 Jun 29. [Epub ahead of print] PubMed PMID: 20591820.
2: Penel N, Watelle F, Vanhuyse M, Adenis A. [Treatment of adult patients with metastatic sarcoma: current shift in concepts]. Bull Cancer. 2010 Jun 1;97(6):687-91. French. PubMed PMID: 20462829.
3: Rodriguez-Pascual J, Cheng E, Maroto P, Duran I. Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs. 2010 Jun;21(5):478-86. Review. PubMed PMID: 20401967.
4: Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol. 2010 Apr;7(4):209-19. Epub 2010 Mar 16. PubMed PMID: 20234352.
5: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Nov;31(9):597-633. PubMed PMID: 20094643.
6: Gibbons JJ, Abraham RT, Yu K. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol. 2009 Dec;36 Suppl 3:S3-S17. Review. PubMed PMID: 19963098.
7: Sessa C, Tosi D, ViganÃ² L, Albanell J, Hess D, Maur M, Cresta S, Locatelli A, Angst R, Rojo F, Coceani N, Rivera VM, Berk L, Haluska F, Gianni L. Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel. Ann Oncol. 2010 Jun;21(6):1315-22. Epub 2009 Nov 9. PubMed PMID: 19901013.
8: Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characteriza