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| 1mg |
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Purity: ≥98%
MS4077 is a potent PROTAC degrader of anaplastic lymphoma kinase (ALK) with a Kd of 37 nM for binding affinity to ALK. MS4077 and MS4078 potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, MS4077 and MS4078 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. This study paved the way for developing the next generation of ALK PROTACs.
| ln Vitro |
Suspension is effectively suspended by MS4077. The IC50 for SU-DHL-1 cell resuspension at a concentration of MS4077 (10-3-1 μM; 3 days) is 46 ± 4 nM. NCI-H2228 cells respond to MS4077 with a lower fat body mass (10-2-100.5 μM; 3 days) than SU-DHL-1 cells [1]. In SU-DHL-1 and NCI-H2228, MS4077 efficiently lowers the levels of ALK fusion protein and suppresses ALK autophosphorylation as well as downstream STAT3 phosphorylation-dependent way. After 16 hours of treatment, MS4077 decreased the levels of NPM-ALK protein in SU-DHL-1 cells, with a DC50 (50% phosphorylation) value of 3±1 nM. The phosphorylation of STAT3 Y705 and ALK Y1507 is inhibited at a rate greater than 90% at 100 nM. After 16 hours, MS4077 treatment decreased EML4-ALK protein levels in NCI-H2228 cells with a comparable DC50 of 34±9 nM. Assay for cell viability at a dose of 100 nM [1]
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: SU-DHL-1 and NCI-H2228 Cell Tested Concentrations: 10-3, 10-2.5, 10, NCI-H2228 cells diminished EML4-ALK protein by more than 90% level[1]. SU-DHL-1 cells were -2, 10-1.5, 10-1, 10-0.5 and 1 μM; NCI-H2228 cells were incubated at 10-2, 10-1.5, 10-1, 10-0.5, 1, 100.5 μM Incubation Duration: 3 days Experimental Results: Inhibits SU-DHL-1 cell proliferation (IC50=46 ± 4 nM). NCI-H2228 cells were less sensitive to proliferation than SU-DHL-1 cells. Western Blot Analysis[1] Cell Types: SU-DHL-1 and NCI-H2228 Cell Tested Concentrations: 1, 3, 10, 30 and 100 μM for SU-DHL-1 cells; 3, 10, 30, 100 μM for NCI-H2228 cells 60 and 100 μM Incubation Duration: 16 hrs (hours) Experimental Results: NPM-ALK protein levels were diminished in SU-DHL-1 cells with DC50 as high as 3 ± 1 nM. diminished EML4-ALK protein levels in NCI-H2228 cells with a similar DC50 of 34 ± 9 nM. |
| References |
| Molecular Formula |
C55H72CLN9O13S
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|---|---|
| Molecular Weight |
1134.73
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| Exact Mass |
1133.465
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| CAS # |
2230077-10-6
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| PubChem CID |
137628669
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| Appearance |
Yellow to green solid powder
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| LogP |
5.9
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
19
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| Rotatable Bond Count |
31
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| Heavy Atom Count |
79
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| Complexity |
2050
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(CC(NCCOCCOCCOCCOCCOCCNC2=CC=CC3=C2C(=O)N(C2CCC(=O)NC2=O)C3=O)=O)CCC(C2=CC(OC(C)C)=C(NC3=NC=C(Cl)C(NC4=CC=CC=C4S(C(C)C)(=O)=O)=N3)C=C2C)CC1
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| InChi Key |
VEKJQNCZEPLNJF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C55H72ClN9O13S/c1-35(2)78-46-32-40(37(5)31-44(46)61-55-59-33-41(56)51(63-55)60-42-10-6-7-12-47(42)79(71,72)36(3)4)38-15-19-64(20-16-38)34-49(67)58-18-22-74-24-26-76-28-30-77-29-27-75-25-23-73-21-17-57-43-11-8-9-39-50(43)54(70)65(53(39)69)45-13-14-48(66)62-52(45)68/h6-12,31-33,35-36,38,45,57H,13-30,34H2,1-5H3,(H,58,67)(H,62,66,68)(H2,59,60,61,63)
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| Chemical Name |
2-[4-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-methyl-5-propan-2-yloxyphenyl]piperidin-1-yl]-N-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]acetamide
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| Synonyms |
MS-4078; MS4078; MS 4078
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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 : ~110 mg/mL (~96.94 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 6 mg/mL (5.29 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 60.0 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: ≥ 6 mg/mL (5.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 60.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8813 mL | 4.4063 mL | 8.8127 mL | |
| 5 mM | 0.1763 mL | 0.8813 mL | 1.7625 mL | |
| 10 mM | 0.0881 mL | 0.4406 mL | 0.8813 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.
Eur J Med Chem.2018 May 10;151:304-314. |
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