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Purity: ≥98%
MI-773 (2'S,3R isomer, SAR405838) is a novel, potent, specific and orally bioavailable small molecule antagonist of MDM2/piro-oxindole HDM2 (Murine double minute 2/human double minute 2) with a Ki value of 0.88 nM. There may be some anticancer properties. Wild-type p53, a tumor suppressor, is primarily negatively regulated by MDM2, a protein. The p53 trans-activation domain (TAD) is blocked by MDM2, an E3 ubiquitin ligase that also promotes p53 degradation.
| Targets |
MDM2 (Ki = 0.88 nM); MDM2 (Kd = 8.2 nM)
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| ln Vitro |
SAR405838 (MI-77301) potently inhibits cell growth in cancer cell lines, including SJSA-1 (IC50, 0.092 μM), RS4;11 (IC50, 0.089 μM), LNCaP (IC50, 0.27 μM), and HCT-116 (IC50, 0.20 μM) cells, and displays high selectivity over cancer cell lines with mutated or deleted p53, including SAOS-2 (IC50, >10 μM), PC-3 (IC50, >10 μM), SW620 (IC50, >10 μM), and HCT-116 (p53-/-) (IC50, >20 μM) cells[1].
SAR405838 has a modestly reduced potency when compared to the control RS4;11 cell line, but it still effectively inhibits cell growth and induces dose-dependent apoptosis in the ABTR1 and ABTR2 sublines[2]. |
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| ln Vivo |
SAR405838 inhibits the growth of tumors completely or permanently in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer at dose schedules that are well tolerated. Surprisingly, SAR405838 only requires one oral dose to completely reverse tumor growth in the SJSA-1 model. MI-773 (p.o.) effectively inhibits tumor growth in a dose-dependent manner in the SJSA-1 osteosarcoma, acute lymphoblastic leukemia RS4;11, LNCaP prostate cancer, and HCT-116 colon cancer xenograft model (10 mg/kg, 30 mg/kg, 50 mg/kg, 100 mg/kg, and 200 mg/kg)[1].
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| Enzyme Assay |
Using a Fluorescence-polarization (FP) binding assay, binding affinities of MDM2 inhibitors and p53 peptide to MDM2 protein are assessed. MI-773's binding affinities to Bcl-2, Bcl-xL, Mcl-1, and β-catenin are assessed using a competitive FP-based assay, and its affinity for MDMx is assessed using Biolayer Interferometry technology.
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| Cell Assay |
In a water-soluble tetrazolium-based assay, cell growth inhibition activity is assessed. Trypan blue staining is used to measure cell death, and a kit for staining with Annexin V-FLUOS determines apoptosis.
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| Animal Protocol |
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| References |
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| Additional Infomation |
SAR405838 has been used in trials studying the treatment of Neoplasm Malignant.
p53-HDM2 Interaction Inhibitor MI-773 is an orally available spiro-oxindole HDM2 (human double minute 2) antagonist with potential antineoplastic activity. Upon oral administration, the p53-HDM2 protein-protein interaction inhibitor MI-773 binds to HDM2, preventing the binding of the HDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this HDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored, which may result in the restoration of p53 signaling and lead to the p53-mediated induction of tumor cell apoptosis. HDM2, a zinc finger protein and a negative regulator of the p53 pathway, is often overexpressed in cancer cells. It has been implicated in cancer cell proliferation and survival. |
| Molecular Formula |
C29H34CL2FN3O3
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| Molecular Weight |
562.50
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| Exact Mass |
561.196
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| Elemental Analysis |
C, 61.92; H, 6.09; Cl, 12.60; F, 3.38; N, 7.47; O, 8.53
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| CAS # |
1303607-60-4
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| Related CAS # |
SAR405838-d10
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| PubChem CID |
53476877
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
732.1±60.0 °C at 760 mmHg
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| Flash Point |
396.6±32.9 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.627
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| LogP |
5.79
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
38
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| Complexity |
895
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| Defined Atom Stereocenter Count |
4
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| SMILES |
O=C([C@H](N[C@H]1CC(C)(C)C)[C@H](C2=CC=CC(Cl)=C2F)[C@@]31C(NC4=C3C=CC(Cl)=C4)=O)N[C@@H]5CC[C@@H](O)CC5
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| InChi Key |
IDKAKZRYYDCJDU-AEPXTFJPSA-N
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| InChi Code |
InChI=1S/C29H34Cl2FN3O3/c1-28(2,3)14-22-29(19-12-7-15(30)13-21(19)34-27(29)38)23(18-5-4-6-20(31)24(18)32)25(35-22)26(37)33-16-8-10-17(36)11-9-16/h4-7,12-13,16-17,22-23,25,35-36H,8-11,14H2,1-3H3,(H,33,37)(H,34,38)/t16?,17?,22-,23-,25+,29+/m0/s1
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| Chemical Name |
(2'R,3R,3'S,5'S)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-N-(4-hydroxycyclohexyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carboxamide
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| Synonyms |
MI773; MI-773; MI 773; MI 77301; MI77301; MI-77301; SAR-405838; SAR 405838; SAR405838
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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: (1). This product is not stable in solution, please use freshly prepared working solution for optimal results. (2). Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.44 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 (4.44 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 25.0 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: ≥ 2.5 mg/mL (4.44 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 | 1.7778 mL | 8.8889 mL | 17.7778 mL | |
| 5 mM | 0.3556 mL | 1.7778 mL | 3.5556 mL | |
| 10 mM | 0.1778 mL | 0.8889 mL | 1.7778 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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