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| 25mg |
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| 100mg |
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Purity: ≥98%
Ridaforolimus (also known as deforolimus, AP-23573; MK-8669) is a novel, potent, investigational and selective mTOR inhibitor with potent antitumor properties. Although ridaforolimus is not a prodrug, it inhibits mTOR and FKBP12 similarly to rapamycin, with an IC50 of 0.2 nM in the HT-1080 cell line. A key regulator of protein synthesis, cell proliferation, cell cycle progression, and cell survival, mTOR integrates signals from proteins like PI3K, AKT, and PTEN that are known to play a role in cancer. By preventing cell growth, division, metabolism, and angiogenesis, mTOR inhibition has a starvation-like effect on cancer cells. In a clinical trial for advanced soft tissue and bone sarcoma, it showed promising results.
| Targets |
FKBP12; mTOR (IC50 = 0.2 nM)
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|---|---|
| ln Vitro |
Deforolimus treatment of HT-1080 cells results in a dose-dependent inhibition of phosphorylation of both S6 and 4E-BP1, with IC50 values of 0.2 nM and 5.6 nM, respectively. This treatment also causes a reduction in cell size, an increase in the percentage of cells in the G1 phase of the cell cycle, and an inhibition of glucose uptake. Deforolimus exhibits notable antiproliferative activity in a variety of cell lines, with an EC50 range of 0.2–2.3 nM. Deforolimus dose-dependently inhibits the production of VEGF with high potency and specificity. [1] Human NSCLC cell lines with IC30 values of 2.45-8.83 nM with the exception of H157, which has an IC30 of >20 nM, are significantly suppressed in terms of growth when treated with deforolimus. In A549, H1703, and H157 cells, deforolimus treatment (2.8–5.9 nM) significantly dephosphorylates p70S6KThr389 (apart from H1666, which may express a resistant variant of mTORC1) and increases phosphorylation of pAKTser473 and pAKTThr308 in A549 and H1703 cells). In lung cancer cell lines, deforolimus combined with the MEK inhibitors CI-1040 or PD0325901 exhibits dose-dependent synergism that is linked to the suppression of cell proliferation rather than the enhancement of cell death. This is characterized by the inhibition of ribosomal biogenesis by 40% within 24 hours and a decreased polysome/monosome ratio. [2]
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| ln 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]
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| Enzyme Assay |
HT-1080 cells are treated with increasing concentrations of Deforolimus (0-100 nM) for 2 hours, prior to harvest. Denaturing lysis buffer is used to extract cellular lysates, and the resolved samples are then run on SDS-PAGE and transferred to PVDF membranes. Following blocking, primary antibodies are applied to the membranes for 1 hour, followed by secondary antibodies that have been HRP-conjugated for the same amount of time at room temperature. Enhanced chemiluminescence and autoradiography, which involves exposure to X-ray film, are used to identify immunoreactive proteins. The phosphorylation of ribosomal proteins S6 and 4E-BP1 (p-S6 and p-4E-BP1, respectively) is used to calculate the IC50.
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| Cell Assay |
Cells are seeded at 2-3 × 104/mL, and serial dilutions of Deforolimus are added after 2 hours, for at least three cell doublings (72-120 hours). The CellTiter 96 Aqueous Nonradioactive Cell Proliferation Assay and Sulforhodamine B Assays are used to measure the effects of deforolimus. Because rapamycin and its derivatives do not significantly impede cell proliferation, Deforolimus's growth effects are classified as IC30.
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| Animal Protocol |
Mice: Different treatment groups are assigned to animals that have tumors that fall within the acceptable size range. Ridaforolimus is given intravenously (i.p.) on 2 different treatment schedules: (a) daily, 5 days straight every other week; and (b) once per week. The dosages are 3 and 10 mg/kg. The untreated group is the control.
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| References | |
| Additional Infomation |
Ridaforolimus is a small molecule and non-prodrug analogue of the lipophilic macrolide antibiotic rapamycin with potential antitumor activity. Ridaforolimus binds to and inhibits the mammalian target of rapamycin (mTOR), which may result in cell cycle arrest and, consequently, the inhibition of tumor cell growth and proliferation. Upregulated in some tumors, mTOR is a serine/threonine kinase involved in regulating cellular proliferation, motility, and survival that is located downstream of the PI3K/Akt signaling pathway.
Drug Indication Investigated for use/treatment in solid tumors, sarcoma, cancer/tumors (unspecified), endometrial cancer, prostate cancer, and bone metastases. Mechanism of Action Deforolimus inhibits the mammalian target of rapamycin (mTOR), a serine kinase of the phosphatidylinositol-3-kinase (PI3K) family that regulates protein synthesis, affecting cell growth and proliferation. mTOR is a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways which cancer cells need to proliferate. |
| Molecular Formula |
C53H84NO14P
|
|---|---|
| Molecular Weight |
990.22
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| Exact Mass |
989.562
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| Elemental Analysis |
C, 64.29; H, 8.55; N, 1.41; O, 22.62; P, 3.13
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| CAS # |
572924-54-0
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| Related CAS # |
572924-54-0
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| PubChem CID |
11520894
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| Appearance |
White to light yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
996.2±75.0 °C at 760 mmHg
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| Melting Point |
95-98ºC
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| Flash Point |
556.3±37.1 °C
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| Vapour Pressure |
0.0±0.6 mmHg at 25°C
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| Index of Refraction |
1.539
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| LogP |
3.12
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
14
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
69
|
| Complexity |
1940
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| Defined Atom Stereocenter Count |
15
|
| SMILES |
O=C([C@@]1(O)[C@@H](CC[C@@H](C[C@@H](/C(C)=C/C=C/C=C/[C@H](C[C@@H](C)C([C@@H]([C@@H](/C(C)=C/[C@H]2C)O)OC)=O)C)OC)O1)C)C(N3CCCC[C@H]3C(O[C@@H](CC2=O)[C@@H](C[C@@H]4C[C@H]([C@H](OP(C)(C)=O)CC4)OC)C)=O)=O
|
| InChi Key |
BUROJSBIWGDYCN-QHPXJTPRSA-N
|
| InChi Code |
InChI=1S/C53H84NO14P/c1-32-18-14-13-15-19-33(2)44(63-8)30-40-23-21-38(7)53(61,67-40)50(58)51(59)54-25-17-16-20-41(54)52(60)66-45(35(4)28-39-22-24-43(46(29-39)64-9)68-69(11,12)62)31-42(55)34(3)27-37(6)48(57)49(65-10)47(56)36(5)26-32/h13-15,18-19,27,32,34-36,38-41,43-46,48-49,57,61H,16-17,20-26,28-31H2,1-12H3/b15-13+,18-14-,33-19+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1
|
| Chemical Name |
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24Z,26E,28E,30S,32S,35R)-12-[(2R)-1-[(1S,3R,4R)-4-dimethylphosphoryloxy-3-methoxycyclohexyl]propan-2-yl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
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| Synonyms |
AP23573; Deforolimus; MK-8669; AP23573; AP 23573; AP-23573; MK8669; MK 8669; MK-8669; Deforolimus; Ridaforolimus
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~198 mg/mL (~200 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.52 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 5% DMSO+40% PEG 300+5% Tween 80+50% H2O: 10mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0099 mL | 5.0494 mL | 10.0988 mL | |
| 5 mM | 0.2020 mL | 1.0099 mL | 2.0198 mL | |
| 10 mM | 0.1010 mL | 0.5049 mL | 1.0099 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Pharmacokinetics of Ridaforolimus (MK-8669) in Chinese Participants (MK-8669-059)
CTID: NCT01380184
Phase: Phase 1 Status: Completed
Date: 2019-04-19
Ridaforolimus attenuates mTOR signaling, resulting in cell shrinkage, cytostatic, and metabolic effects. Mol Cancer Ther, 2011, 10(6), 1059-1071. |
Ridaforolimus treatment inhibits tumor cell proliferation independent of PTEN status or AKT activation. |
In vivo activity and efficacy of ridaforolimus. Mol Cancer Ther, 2011, 10(6), 1059-1071. |
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