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MS-177 is a novel PROTAC EZH2 degarder based on the EZH2 inhibitor C24 and the CRBN ligand pomalidomid. It degrades EZH2 e with DC50 of 0.2 uM in EOL-1 cells. MS-177 is a PROTAC targeting the multifaceted tumorigenic functions of EZH2 and presents an attractive strategy for treating EZH2-dependent cancers.
| ln Vitro |
EZH2-PRC2's enzymatic activity is inhibited by MS177 (IC50: 7 nM)[1]. In HeLa cells, MS177 (5 μM, 24 hours) lowers H3K27me3 and raises H3K27 activity [1]. In EOL-1 cells, MS177 (0.1–5 μM, 16 hours) efficiently breaks down cellular EZH2-PRC2 and prevents global H3K27me3 [1]. In EOL-1 and MV4 cells, MS177 (0.1–5 μM, 16 hours) causes Myc degradation [1]. In a panel of MLL-r leukemia cells and AML patient samples, MS177 (4 days) demonstrated antiproliferative effects with an IC50 below 2 μM [1]. MS177 (0.5-2.5 μM, 24 hours) inhibits MV4;11 cells' capacity to form colonies [1]. In MOLM-13 cells, MS177 (0.5-2.5 μM, 24 hours) causes apoptosis and slows down the course of the cell cycle [1].
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| ln Vivo |
MS177 (100 mg/kg, intraperitoneally, BID, 6 days) suppresses tumor growth in the PDX animal model of MLL-r AML and in the subcutaneous xenograft MLL-r leukemia model [1]. MS177 (50 mg/kg, i.p.) achieves plasma concentrations of around 1 μM in male Swiss albino mice [1]. MS177 (100 mg/kg, i.p., BID, 6 days a week; 200 mg/kg, i.p., 3 days a week BID) was well tolerated in mice with no evident harm [1] .
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| Cell Assay |
Cell viability assay[1]
Cell Types: AML Cell Types: MV4;11, MOML-13, RS4;11, KOPN-8 THP-1, EOL-1 (MLL-r cells) Control Cell Types: K562 (CML cells) Patient sample: AML cells Tested Concentrations: approximately 0-100 μM Incubation Duration: 4 days Experimental Results: Inhibited cell proliferation, IC50 for MLL-r cells was 0.1-0.57 μM, patient sample was 0.09-1.35 μM, K562 cells >100 μM. Western Blot Analysis[1] Cell Types: EOL-1 Cell Tested Concentrations: 0.1, 0.5, 1, 2.5, 5 μM Incubation Duration: 16 hrs (hours) Experimental Results: Depletion of EZH2, EED and SUZ12 in a concentration-dependent manner and inhibition of global H3K27me3. |
| Animal Protocol |
Animal/Disease Models: PDX animal model of MLL-r AML [1]
Doses: 100 mg/kg Route of Administration: intraperitoneal (ip) injection, BID, for 6 days. Experimental Results: Inhibited tumor growth and prolonged survival. |
| References |
| Molecular Formula |
C48H55N11O8
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|---|---|
| Molecular Weight |
914.02
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| Exact Mass |
913.42
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| Elemental Analysis |
C, 63.07; H, 6.07; N, 16.86; O, 14.00
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| CAS # |
2225938-86-1
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| Related CAS # |
2225938-86-1;2225938-88-3 (isomer);
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| PubChem CID |
139413605
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
17
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| Heavy Atom Count |
67
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| Complexity |
1950
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LRMNSTSNSCJHGZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C48H55N11O8/c1-28(2)59-39-24-32(23-34(36(39)27-53-59)44(62)52-26-35-29(3)22-30(4)54-45(35)63)31-8-10-40(51-25-31)57-18-16-56(17-19-57)15-13-50-41(60)12-20-67-21-14-49-37-7-5-6-33-43(37)48(66)58(47(33)65)38-9-11-42(61)55-46(38)64/h5-8,10,22-25,27-28,38,49H,9,11-21,26H2,1-4H3,(H,50,60)(H,52,62)(H,54,63)(H,55,61,64)
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| Chemical Name |
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[6-[4-[2-[3-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]propanoylamino]ethyl]piperazin-1-yl]pyridin-3-yl]-1-propan-2-ylindazole-4-carboxamide
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| Synonyms |
MS177; MS 177; MS-177;
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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 : ~125 mg/mL (~136.76 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (2.28 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0941 mL | 5.4703 mL | 10.9407 mL | |
| 5 mM | 0.2188 mL | 1.0941 mL | 2.1881 mL | |
| 10 mM | 0.1094 mL | 0.5470 mL | 1.0941 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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