| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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| 50mg | |||
| 100mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
HDM201 targets the MDM2 protein (human double minute 2 homolog), binding to the p53-binding site of MDM2 with picomolar affinity and a selectivity ratio of more than 1000-fold against MDM4. By disrupting the MDM2-p53 interaction, it prevents MDM2-mediated proteasomal degradation of p53, thereby restoring p53 signaling and tumor cell apoptosis.
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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. In human tumor cells with p53 wild-type, it causes a robust cell cycle arrest and apoptosis. A panel of cancer cell lines that HDM201 exhibits high selectivity toward.
In vitro, HDM201 binds to the p53-binding site of MDM2 protein, disrupting the interaction between p53 and MDM2 and activating the p53 pathway. In human tumor cells with wild-type p53, it causes robust cell cycle arrest and apoptosis. It exhibits high selectivity toward a panel of cancer cell lines. |
| ln Vivo |
Treatment was initiated when the tumors engrafted in the flank were at least 150 mm3. The enrollment process was random. With the measurements of tumor volumes at the beginning of treatment, efficacy studies, tumor response, and relapse were reported. Two times per week, at intervals of 3 days and 4 days alternately, HDM201 was given orally at a dose of 100 mg/kg in a solution of 0.5% methylcellulose and 0.1% Tween 80. Vehicle was produced using the formulation. Early in the morning, treatments were given.
In vivo, HDM201 was administered orally at 100 mg/kg in 0.5% methylcellulose and 0.1% Tween 80 twice weekly when tumors reached at least 150 mm³ in flank xenograft models. Tumor volumes were measured at treatment initiation, and efficacy, tumor response, and relapse were reported. |
| Enzyme Assay |
The binding affinity of HDM201 for MDM2 is determined using cell-free radioligand binding or surface plasmon resonance (SPR) assays with recombinant MDM2 protein. Competitive displacement of a labeled p53-derived peptide is measured, and IC50 or Ki values are calculated from dose-response curves to quantify the compound's potency in disrupting the MDM2-p53 interaction.
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| Cell Assay |
The in vitro combination screen was carried out on cancer cell lines at Horizon Discovery (Cambridge, MA), and data analysis was done as previously mentioned. Here, we concentrated our data analysis on combinations involving CGM097, a member of an earlier generation of selective TP53-MDM2 inhibitors. Various concentrations of CGM097 and 25 additional compounds were applied to a total of 485 cancer cell lines. We combined the data on TP53 mutation status and distinguished between cell lines that did not have TP53 mutations and cell lines that did. We evaluated the synergistic effects of combining HDM201 and A-1155463 as previously mentioned.
Cell-based assays for HDM201 are conducted on cancer cell lines with wild-type TP53. Cells are treated with varying concentrations of HDM201, and p53 pathway activation is assessed by measuring downstream target gene expression (e.g., p21, MDM2) via qPCR or Western blot. Apoptosis and cell cycle arrest are evaluated by flow cytometry and cell viability assays. |
| 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 are performed in mouse flank xenograft models using cancer cell lines with wild-type TP53. When tumors reach approximately 150 mm³, HDM201 is administered orally at 100 mg/kg twice weekly in a vehicle of 0.5% methylcellulose and 0.1% Tween 80. Tumor volumes are measured twice weekly to assess efficacy, tumor response, and relapse. |
| ADME/Pharmacokinetics |
HDM201 is orally bioavailable. It has high affinity for MDM2 in the picomolar range. The molecular formula is C₂₆H₂₄Cl₂N₆O₄ with a molecular weight of 555.41. Detailed pharmacokinetic parameters such as half-life, Cmax, and oral bioavailability in preclinical species are not fully disclosed in the available literature.
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| Toxicity/Toxicokinetics |
No detailed toxicity data are available in the provided references. However, HDM201 is currently in Phase I clinical trials for cancer treatment, indicating that it has progressed through preclinical safety evaluation. As an MDM2 inhibitor, potential toxicities may include on-target effects related to p53 activation in normal tissues, which would be carefully monitored in clinical studies.
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| References | |
| Additional Infomation |
HDM201 (also known as Siremadlin and NVP-HDM201) is an investigational compound not yet approved for clinical use. It is being evaluated in Phase I clinical trials for the treatment of various cancers. By inhibiting the MDM2-p53 interaction, it represents a promising therapeutic strategy for restoring p53 tumor suppressor function in tumors that retain wild-type TP53.
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| Molecular Formula |
C26H24CL2N6O4
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|---|---|
| Molecular Weight |
555.41
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| Exact Mass |
554.123
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| 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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| LogP |
3.6
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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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| SMILES |
CC(C)N1C2=C(C(=O)N([C@@H]2C3=CC=C(C=C3)Cl)C4=CC(=CN(C4=O)C)Cl)N=C1C5=CN=C(N=C5OC)OC
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| InChi Key |
AGBSXNCBIWWLHD-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C26H24Cl2N6O4/c1-13(2)33-21-19(30-22(33)17-11-29-26(38-5)31-23(17)37-4)25(36)34(18-10-16(28)12-32(3)24(18)35)20(21)14-6-8-15(27)9-7-14/h6-13,20H,1-5H3/t20-/m1/s1
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| Chemical Name |
(4R)-5-(5-chloro-1-methyl-2-oxopyridin-3-yl)-4-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4H-pyrrolo[3,4-d]imidazol-6-one
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| Synonyms |
HDM-201; HDM 201; HDM201; NVP-HDM 201; NVP-HDM201; NVP-HDM-201
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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) |
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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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03940352 | Active Recruiting |
Drug: HDM201 Drug: Venetoclax |
Acute Myeloid Leukemia (AML) High-risk Myelodysplastic Syndrome (MDS) |
Novartis Pharmaceuticals | June 24, 2019 | Phase 1 |
| NCT05599932 | Recruiting | Drug: Siremadlin | Hepatic Impairment | Novartis Pharmaceuticals | December 2, 2022 | Phase 1 |
| NCT05180695 | Recruiting | Drug: Pazopanib Drug: HDM201 |
Advanced Soft-tissue Sarcoma Metastatic Soft-tissue Sarcoma |
Centre Leon Berard | April 15, 2022 | Phase 1 Phase 2 |
| NCT03714958 | Completed | Drug: HDM201 Drug: Trametinib |
Colorectal Cancer Advanced Cancer |
Centre Leon Berard | December 20, 2018 | Phase 1 |
| NCT02343172 | Completed | Drug: HDM201 Drug: LEE011 |
Liposarcoma | Novartis Pharmaceuticals | March 13, 2015 | Phase 1 |
 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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