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| 5mg |
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Purity: ≥98%
| Targets |
HDM201 R Enantiomer targets the MDM2 protein (human double minute 2 homolog), acting as a potent and highly specific inhibitor of the MDM-2/p53 interaction. It has high affinity for MDM2 in the picomolar range and a selectivity ratio of more than 10000-fold versus MDM4. By binding to MDM2, it prevents MDM2-mediated degradation of p53.
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| ln Vitro |
In vitro activity: HDM201 acts by binding to the p53 binding-site of the Mdm2 protein, thereby disrupting the interaction of the two proteins (p53 and Mdm2) and leading to the activation of the p53 pathway. It induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. HDM201 exhibits highly selectivity across a panel of cancer cell lines
Kinase Assay: Cell Assay: The in vitro combination screen was performed at Horizon Discovery (Cambridge, MA) on cancer cell lines, and data analysis was performed as described previously. Here we focused the data analysis on combinations with CGM097, a previous class of selective TP53-MDM2 inhibitors. A total of 485 cancer cell lines were treated with varying concentrations of CGM097 and for 25 other compounds. We integrated the information on TP53 mutation status and differentiated cell lines with no TP53 mutation from cell lines with TP53 alteration. We assessed the synergistic effect of combinations of HDM201and A-1155463 as described previously. As the R enantiomer of Siremadlin, this compound exhibits potent biological activity in disrupting the MDM-2-mediated degradation of p53, thereby promoting p53-dependent tumor suppression. It is a highly specific inhibitor of the MDM-2/p53 interaction. Detailed in vitro activity data specific to the R enantiomer are limited. |
| ln Vivo |
Treatment was initiated when the tumors engrafted in the flank were at least 150 mm3. Random enrollment was applied. Efficacy studies, tumor response, and relapse were reported with the measures of tumor volumes at the start of treatment. HDM201 was administered at 100 mg/kg in 0.5% methylcellulose and 0.1% Tween 80 orally twice a week, with alternating intervals of 3 d and 4 d. Vehicle was generated according to the formulation. Treatments were administered in the morning.
In vivo activity data specific to the HDM201 R Enantiomer are not detailed in the available literature. However, as the R enantiomer of the active pharmaceutical ingredient HDM201 (Siremadlin), it is expected to share similar in vivo pharmacological properties, including oral bioavailability and antitumor efficacy in MDM2-dependent tumor models. |
| Enzyme Assay |
Cell-free binding assays for the HDM201 R Enantiomer would be conducted similarly to the racemic or other enantiomeric forms, using radioligand binding or SPR-based methods with recombinant MDM2 protein. Displacement of a labeled p53-derived peptide would be measured to determine binding affinity and potency for disrupting the MDM2-p53 interaction.
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| Cell Assay |
Cellular assays for the R enantiomer would employ cancer cell lines with wild-type TP53, treating cells with varying concentrations of the compound. Activation of the p53 pathway would be assessed by measuring downstream target gene expression, and antiproliferative effects would be evaluated through cell viability and apoptosis assays.
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| Animal Protocol |
HDM201 was administered at 100 mg/kg in 0.5% methylcellulose and 0.1% Tween 80 orally twice a week
Mouse In vivo animal studies for the R enantiomer would follow protocols similar to those for HDM201, using mouse flank xenograft models with wild-type TP53 cancer cell lines. The compound would be administered orally, and tumor growth inhibition would be monitored to evaluate efficacy in restoring p53-mediated tumor suppression. |
| ADME/Pharmacokinetics |
The HDM201 R Enantiomer has the molecular formula C₂₆H₂₄Cl₂N₆O₄ and a molecular weight of 555.41. As the R enantiomer of Siremadlin, it is expected to be orally bioavailable. Detailed pharmacokinetic parameters specific to the R enantiomer are not available, but it is anticipated to share similar absorption and disposition characteristics with HDM201.
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| Toxicity/Toxicokinetics |
No specific toxicity data for the HDM201 R Enantiomer are available in the provided references. Safety profiles would be expected to be similar to those of the parent compound HDM201, which has progressed to clinical trials. Preclinical toxicology studies would have been conducted to support its evaluation.
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| References |
Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156;Bioorg Med Chem Lett.2016 Oct 1;26(19):4837-4841.
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| Additional Infomation |
HDM201 R Enantiomer (Siremadlin R Enantiomer) is a research-grade compound used for studying the MDM2-p53 interaction. It is one of the enantiomeric forms of HDM201, a clinical-stage MDM2 inhibitor. This compound is primarily used in research settings to investigate the stereochemical aspects of MDM2 inhibition and p53 pathway activation.
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| Molecular Formula |
C26H24CL2N6O4
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| Molecular Weight |
555.41
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| Exact Mass |
| 554.1236 | |
| CAS # |
1448867-42-2
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| Related CAS # |
Siremadlin;1448867-41-1
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| PubChem CID |
71679278
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
38
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| Complexity |
987
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| Defined Atom Stereocenter Count |
1
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| Synonyms |
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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 |
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| 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) |
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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 | 1.8005 mL | 9.0024 mL | 18.0047 mL | |
| 5 mM | 0.3601 mL | 1.8005 mL | 3.6009 mL | |
| 10 mM | 0.1800 mL | 0.9002 mL | 1.8005 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.
Bcl-xL modulates the sensitivity of cell lines to TP53-MDM2 inhibition.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156. |
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Bcl-xL expression confers resistance to HDM201.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156. |
 Characterization of genetic modifications in HDM201-resistant tumors.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156. |
 Response and resistance to HDM201 TP53-MDM2 inhibitor allografted mice.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156. |
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 Characterization of response to HDM201 treatment of RosaPB/+;ATP2/+;Arf−/−allografted tumors.Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156. |
 Resistance mechanisms identified in HDM201-resistant tumors.Representation of major PB transposon insertions found significantly enriched in RosaPB/+;ATP2/+;Arf−/−HDM201-resistant implanted tumors compared with untreated tumors (n= 95 tumors with differential PB insertions).Proc Natl Acad Sci U S A.2017 Mar 21;114(12):3151-3156. |
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