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Milademetan tosylate hydrate (also called DS3032b; DS-3032), the tosylate salt and hydrated form of Milademetan, is a potent, selective and orally bioactive MDM2 inhibitor with potential antitumor activity.
Milademetan (also known as DS-3032, DS-3032b, or RAIN-32) is an orally available, potent, and selective small molecule inhibitor of the murine double minute 2 (MDM2) protein. It functions as an MDM2-p53 interaction antagonist. By binding to MDM2 and preventing its interaction with the tumor suppressor p53, milademetan stabilizes p53, restoring its transcriptional activity and inducing apoptosis in cancer cells. It has been investigated in clinical trials for various solid tumors, lymphomas, and myeloid malignancies .| 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 .
In wild-type TP53 neuroblastoma cells, meledemetan (DS-3032) preferentially promotes 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 decreases the viability, proliferation, and migration of neuroblastoma cells carrying wild-type TP53 [4]. |
| 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 .
Milademetan (DS-3032b, 50 mg/kg, orally administered) xenografts neuroblastoma cells with functioning TP53, delaying tumor growth and enhancing survival [4]. |
| Enzyme Assay |
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 .
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 |
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 .
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. |
| 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 | |
| Additional Infomation |
Milademetan has been evaluated in multiple clinical trials including MANTRA (phase III in liposarcoma), MANTRA-2 (phase II in MDM2-amplified solid tumors), and MANTRA-4 (planned for combination with atezolizumab). In a phase II trial of MDM2-amplified, TP53-wildtype solid tumors, the objective response rate was 19.4% (6/31), including a patient with endometrial stromal sarcoma who achieved 100% target lesion reduction. The median progression-free survival was 3.5 months . In dedifferentiated liposarcoma, the disease control rate was 58.5% with median PFS of 7.2 months . In myeloid malignancies, clinical efficacy was minimal despite being relatively well-tolerated .
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| Molecular Formula |
C₃₇H₄₄CL₂FN₅O₈S
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|---|---|
| Molecular Weight |
808.74
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| Exact Mass |
807.227
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| CAS # |
2095625-97-9
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| Related CAS # |
Milademetan;1398568-47-2; 2095625-97-9; 1398569-75-9
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| PubChem CID |
89051550
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
54
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| Complexity |
1290
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CC1=CC=C(C=C1)S(=O)(=O)O.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.O
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| InChi Key |
WPJOGWGXMTUHPW-CIPNXXNHSA-N
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| InChi Code |
InChI=1S/C30H34Cl2FN5O4.C7H8O3S.H2O/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;1-6-2-4-7(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);1H2/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''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide mono(4-methylbenzenesulfonate) monohydrate
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| Synonyms |
DS3032b tosylate hydrate; DS-3032b; 4Y0K58UFU2; Milademetan tosylate monohydrate; DS-3032 TOSYLATE MONOHYDRATE; (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''-OXO-1'',2''-DIHYDRODISPIRO(CYCLOHEXANE-1,2'-PYRROLIDINE-3',3''-INDOLE)-5'-CARBOXAMIDE MONO(4-METHYLBENZENESULFONATE) MONOHYDRATE; (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''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide mono(4-methylbenzenesulfonate) monohydrate; DS-3032; DS 3032b; DS 3032; DS3032; DS-3032b tosylate; Milademetan tosylate hydrate
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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: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 : ~50 mg/mL (~61.82 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (6.18 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 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: 5 mg/mL (6.18 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 50.0 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: ≥ 5 mg/mL (6.18 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 | 1.2365 mL | 6.1825 mL | 12.3649 mL | |
| 5 mM | 0.2473 mL | 1.2365 mL | 2.4730 mL | |
| 10 mM | 0.1236 mL | 0.6182 mL | 1.2365 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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