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Milademetan (DS-3032b; DS3032; DS-3032) is a potent, selective and orally bioactive MDM2 inhibitor with potential antitumor activity. DS-3032b binds to, and prevents the binding of MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this MDM2-p53 interaction, the proteosome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored. This results in the restoration of p53 signaling and leads to the p53-mediated induction of tumor cell apoptosis.
| ln Vitro |
In wild-type TP53 neuroblastoma cells, meledemetan (DS-3032) selectively induces the expression of CDKNA1, BAX, and MDM2 while stabilizing TP53 [3]. Treatment with meledemetan (DS-3032b) increases the expression of the TP53 target gene and causes apoptosis, senescence, and G1 cell cycle arrest [3]. Regardless of MYCN status, treatment with meledemetan (DS-3032b, 0-2000 nM) specifically inhibits the viability, proliferation, and migration of neuroblastoma cells harboring wild-type TP53 [4].
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| ln Vivo |
Milademetan (DS-3032b, 50 mg/kg, orally administered) xenografts neuroblastoma cells with functioning TP53, delaying tumor growth and enhancing survival [4].
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| Cell Assay |
Cell viability assay[4]
Cell Types: SK-N-SH, SH-SY5Y, IMR32, IMR5 and LAN5 cell lines. Tested Concentrations: 0-2000 nM. Incubation Duration: 24-72 hrs (hours). Experimental Results: Vitality diminished in a dose- and time-dependent manner. In SK-N-SH, SH-SY5Y, IMR32, IMR5 and LAN5 cell lines (72 hrs (hours)), the IC50 values were 21.9 nM, 17.7 nM, 52.63 nM, 25.7 nM and 44.1 nM, respectively. |
| Animal Protocol |
Animal/Disease Models: SH-SY5Y nude mouse xenograft tumor [4].
Doses: 50 mg/kg. Dosing: po (oral gavage) for 30 days, alternating with 4 days of po (oral gavage) treatment and then 2 days of no treatment (4+2). Experimental Results: The survival rate of the mouse group was Dramatically prolonged. diminished neuroblastoma xenograft tumor growth through activation of TP53 signaling. |
| References | |
| Additional Infomation |
Milademetan is under investigation in clinical trial NCT02319369 (Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)).
Milademetan is an orally available MDM2 (murine double minute 2) antagonist with potential antineoplastic activity. Upon oral administration, milademetan binds to, and prevents the binding of MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this MDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored. This results in the restoration of p53 signaling and leads to the p53-mediated induction of tumor cell apoptosis. MDM2, a zinc finger protein and a negative regulator of the p53 pathway, is overexpressed in cancer cells; it has been implicated in cancer cell proliferation and survival. |
| Molecular Formula |
C₃₀H₃₄CL₂FN₅O₄
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|---|---|
| Molecular Weight |
618.526468753815
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| Exact Mass |
617.197
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| CAS # |
1398568-47-2
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| Related CAS # |
Milademetan tosylate hydrate;2095625-97-9
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| PubChem CID |
73297272
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
840.7±65.0 °C at 760 mmHg
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| Flash Point |
462.2±34.3 °C
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| Vapour Pressure |
0.0±3.1 mmHg at 25°C
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| Index of Refraction |
1.646
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| LogP |
3.54
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
42
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| Complexity |
1090
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CC1(CCC2(CC1)[C@@]3([C@H]([C@@H](N2)C(=O)N[C@@H]4CC[C@H](OC4)C(=O)N)C5=C(C(=NC=C5)Cl)F)C6=C(C=C(C=C6)Cl)NC3=O)C
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| InChi Key |
RYAYYVTWKAOAJF-QISPRATLSA-N
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| InChi Code |
InChI=1S/C30H34Cl2FN5O4/c1-28(2)8-10-29(11-9-28)30(18-5-3-15(31)13-19(18)37-27(30)41)21(17-7-12-35-24(32)22(17)33)23(38-29)26(40)36-16-4-6-20(25(34)39)42-14-16/h3,5,7,12-13,16,20-21,23,38H,4,6,8-11,14H2,1-2H3,(H2,34,39)(H,36,40)(H,37,41)/t16-,20+,21+,23-,30-/m1/s1
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| Chemical Name |
(3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyloxan-3-yl]-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
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| Synonyms |
DS-3032B DS 3032B DS3032B DS-3032 DS 3032 DS3032 Milademetan free base
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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 |
| 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 : ~16.67 mg/mL (~26.95 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (2.70 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 16.7 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: 1.67 mg/mL (2.70 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.67 mg/mL (2.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6167 mL | 8.0837 mL | 16.1674 mL | |
| 5 mM | 0.3233 mL | 1.6167 mL | 3.2335 mL | |
| 10 mM | 0.1617 mL | 0.8084 mL | 1.6167 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.
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