| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Milademetan tosylate (formerly DS3032b; DS3032; DS-3032b; DS-3032), the tosylate salt of Milademetan, is a selective and orally bioavailable inhibitor of MDM2-p53 protein protein interaction with potential anticancer activity.
| Targets |
The primary target of milademetan is MDM2 (murine double minute 2), an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53. Milademetan is a potent and selective inhibitor of the MDM2-p53 protein-protein interaction .
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| ln Vitro |
Milademetan demonstrates potent in vitro activity across various cancer cell lines. It reduces cell viability specifically in TP53 wild-type (WT) cell lines. In Merkel cell carcinoma models, milademetan triggered a rapid and sustained p53 response and showed dose-dependent inhibition of tumor cell growth . Preclinical testing revealed that cell lines with CDKN2A homozygous loss in the context of wild-type TP53 exhibit significantly higher sensitivity, with a median IC50 of 79.5 nM compared to 10,000 nM in cell lines with mutant TP53 or non-homozygous loss of CDKN2A . The compound also showed potent activity against MDM2-amplified, TP53-wildtype laboratory models .
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| ln Vivo |
In vivo, milademetan demonstrated significant anti-tumor activity. It showed dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft (PDX) models of Merkel cell carcinoma . Xenograft models with CDKN2A homozygous loss and wild-type TP53 all demonstrated tumor growth inhibition with milademetan. Furthermore, combination with an anti-PD1 antibody in a colon-26 syngeneic model (with CDKN2A homozygous loss) showed significant enhancement in tumor growth inhibition compared to either agent alone .
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| Enzyme Assay |
While detailed assay protocols are not publicly available in the provided documents, milademetan is characterized as a selective inhibitor of the MDM2-p53 protein-protein interaction. The compound works by binding to MDM2 and preventing its interaction with the transcriptional activation domain of p53, thereby inhibiting the proteasome-mediated enzymatic degradation of p53 .
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| Cell Assay |
In vitro cell assays were performed using cancer cell lines treated with milademetan to assess viability and p53 pathway activation. Cell viability was measured using standard assays, and p53 response was evaluated by assessing downstream target gene expression or protein stabilization. The sensitivity of 215 cancer cell lines to milademetan treatment was evaluated to determine IC50 values based on TP53 and CDKN2A status .
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| Animal Protocol |
Preclinical efficacy was evaluated using xenograft models. Immunocompromised mice were implanted with human tumor cell lines (such as MKL-1) or patient-derived tumor tissue. Milademetan was administered orally, typically once daily, using various intermittent or continuous dosing schedules. Tumor growth inhibition was monitored over time. In combination studies, anti-PD1 antibody was administered via intraperitoneal injection .
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| ADME/Pharmacokinetics |
Milademetan is an orally bioavailable small molecule. In the first-in-human phase I study, pharmacokinetic analyses were conducted to characterize its absorption and exposure profile. The recommended phase II dose and schedule (260 mg once daily on days 1-3 and 15-17 every 28 days, i.e., a 3/14 day intermittent schedule) was selected based on PK/PD data to mitigate dose-limiting toxicities while maintaining efficacy .
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| Toxicity/Toxicokinetics |
The most common grade 3/4 treatment-emergent adverse events observed in clinical trials include thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). An intermittent dosing schedule (3/14 days) significantly reduced the rates of these high-grade hematologic abnormalities (thrombocytopenia: 15.0%, neutropenia: 5.0%, anemia: 0%) while maintaining efficacy. Other reported adverse events included gastrointestinal issues, fatigue, diarrhea, leukopenia, and renal/electrolyte abnormalities .
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| References |
[1].ARYL SULFONOHYDRAZIDES. WO 2017069289 A1. [5]. Predictive gene signatures determine tumor sensitivity to MDM2 inhibition. Cancer Res. 2018 Feb 28. pii: canres.0949.2017. doi: 10.1158/0008-5472. |
| Additional Infomation |
The most common grade 3/4 treatment-emergent adverse events observed in clinical trials include thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). An intermittent dosing schedule (3/14 days) significantly reduced the rates of these high-grade hematologic abnormalities (thrombocytopenia: 15.0%, neutropenia: 5.0%, anemia: 0%) while maintaining efficacy. Other reported adverse events included gastrointestinal issues, fatigue, diarrhea, leukopenia, and renal/electrolyte abnormalities .
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| Molecular Formula |
C37H42CL2FN5O7S
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|---|---|
| Molecular Weight |
790.728089809418
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| Exact Mass |
789.2166034
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| Elemental Analysis |
C, 56.20; H, 5.35; Cl, 8.97; F, 2.40; N, 8.86; O, 14.16; S, 4.05
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| CAS # |
1398569-75-9
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| Related CAS # |
1398568-47-2;1398569-75-9;2095625-97-9 (tosylate hydrate);Milademetan HCl;
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| PubChem CID |
89051543
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
53
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| Complexity |
1290
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| Defined Atom Stereocenter Count |
5
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| SMILES |
ClC1C=CC2=C(C=1)NC([C@@]12[C@@H](C2C=CN=C(C=2F)Cl)[C@H](C(N[C@H]2CO[C@H](C(N)=O)CC2)=O)NC21CCC(C)(C)CC2)=O.S(C1C=CC(C)=CC=1)(=O)(=O)O
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| InChi Key |
NHIUKVHKLJSJEA-LINJWFRASA-N
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| InChi Code |
InChI=1S/C30H34Cl2FN5O4.C7H8O3S/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)42-14-161-6-2-4-7(5-3-6)11(8,9)10/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)2-5H,1H3,(H,8,9,10)/t16-,20+,21+,23-,30-/m1./s1
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| Chemical Name |
(3'R,4'S,5'R)-N-((3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl)-6''-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide
tosylate
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| Synonyms |
DS3032b tosylate; DS-3032b tosylate; DS-3032B; DS-3032 TOSYLATE; UNII-6M27443B0N; 6M27443B0N; DS 3032b; DS3032; DS-3032b; DS-3032; DS 3032; Milademetan tosylate
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2647 mL | 6.3233 mL | 12.6465 mL | |
| 5 mM | 0.2529 mL | 1.2647 mL | 2.5293 mL | |
| 10 mM | 0.1265 mL | 0.6323 mL | 1.2647 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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