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Purity: ≥98%
Siremadlin (formerly also known as NVP-HDM201; NVP-HDM-201; HDM-201; HDM201) is a novel, potent, highly specific and orally bioavailable inhibitor of MDM-2/p53 with potential antitumor activity. It has potential antineoplastic activity as a human double minute 2 homolog (HDM2) inhibitor. Siremadlin prevents the HDM2 protein from attaching to the p53 tumor suppressor protein's transcriptional activation domain. Cancer cells frequently overexpress HDM2, a zinc finger protein that is a negative regulator of the p53 pathway and has been linked to cancer cell survival and proliferatio.
| Targets |
p53-MDM2 interaction
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| ln Vitro |
HDM201 binds to the p53 binding-site of the Mdm2 protein, disrupting the interaction of the two proteins and leading to the activation of the p53 pathway[1].
In human p53 wild-type tumor cells, it causes a robust cell cycle arrest and apoptosis. A variety of cancer cell lines show that HDM201 is highly selective[2]. |
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| ln Vivo |
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| Cell Assay |
At Horizon Discovery (Cambridge, MA), cancer cell lines were subjected to an in vitro combination screen, and data analysis was carried out as previously mentioned. Here, the data analysis was concentrated on combinations involving CGM097, a member of an earlier generation of selective TP53-MDM2 inhibitors. CGM097 and 25 additional compounds were applied to a total of 485 cancer cell lines at various concentrations. We combined the data regarding the presence or absence of TP53 mutations and distinguished between cell lines with and without TP53 mutations. By combining HDM201 and A-1155463 as previously mentioned, we evaluated the synergistic effect.
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| References |
| Molecular Formula |
C26H24CL2N6O4
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|---|---|
| Molecular Weight |
555.41
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| Exact Mass |
554.1236
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| Elemental Analysis |
C, 56.23; H, 4.36; Cl, 12.77; N, 15.13; O, 11.52
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| CAS # |
1448867-41-1
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| Related CAS # |
Siremadlin (R Enantiomer);1448867-42-2
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| Appearance |
Solid powder
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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-FQEVSTJZSA-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-/m0/s1
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| Chemical Name |
(4S)-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 |
HDM201; NVP-HDM201; NVP-HDM-201; HDM 201; HDM-201; NVP HDM 201; 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) |
DMSO: 56.75~100 mg/mL (102.2~180.1 mM)
Ethanol: ~3 mg/mL (~5.4 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.50 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 25.0 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: ≥ 2.5 mg/mL (4.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.50 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (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 | 1.8005 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 |
| NCT04097821 | Active Recruiting |
Drug: Ruxolitinib Drug: Siremadlin |
Myelofibrosis | Novartis Pharmaceuticals | September 26, 2019 | Phase 1 Phase 2 |
| NCT05599932 | Recruiting | Drug: Siremadlin | Hepatic Impairment | Novartis Pharmaceuticals | December 2, 2022 | Phase 1 |
| NCT05447663 | Recruiting | Drug: Siremadlin | Acute Myeloid Leukemia Allogeneic Stem Cell Transplantation |
Novartis Pharmaceuticals | February 23, 2023 | Phase 1 Phase 2 |
| NCT05155709 | Recruiting | Drug: siremadlin Drug: venetoclax |
Acute Myeloid Leukemia | Novartis Pharmaceuticals | May 17, 2022 | Phase 1 Phase 2 |
| NCT05180695 | Recruiting | Drug: Pazopanib Drug: HDM201 |
Advanced Soft-tissue Sarcoma Metastatic Soft-tissue Sarcoma |
Centre Leon Berard | April 15, 2022 | Phase 1 Phase 2 |
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