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| Targets |
MS-177 targets EZH2 for ubiquitination and subsequent proteasomal degradation by simultaneously binding to EZH2 (via the C24 warhead) and the E3 ubiquitin ligase Cereblon (CRBN, via the pomalidomide moiety). This dual-binding event brings EZH2 into close proximity with the ubiquitin-proteasome system, leading to its selective and efficient degradation. It effectively depletes both the canonical EZH2-PRC2 and the noncanonical EZH2-cMyc complexes.
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| 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].
MS-177 potently inhibits the enzymatic activity of the EZH2-PRC2 complex with an IC50 of 7 nM in a biochemical assay. It induces robust EZH2 protein degradation with a DC50 value of 0.2 uM in EOL-1 leukemia cells. This degradation effectively inhibits leukemia cell growth, induces apoptosis, and arrests cell cycle progression. The compound is significantly more effective and potent at suppressing cancer growth than traditional catalytic EZH2 inhibitors. |
| 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] .
In patient-derived xenograft models of acute myeloid leukemia (AML), MS-177 suppresses tumor growth without apparent toxicity. This in vivo efficacy, combined with its ability to deplete EZH2 protein levels, demonstrates its potential as a therapeutic strategy for EZH2-dependent cancers by targeting both the canonical and noncanonical functions of EZH2, which is more effective than simple catalytic inhibition. |
| Enzyme Assay |
The assay uses purified recombinant EZH2-PRC2 complex and a biotinylated histone H3 peptide substrate. Varying concentrations of MS-177 are incubated with the enzyme, SAM (methyl donor), and peptide in reaction buffer. After incubation, the reaction is quenched, and the amount of trimethylated H3K27 is quantified using a TR-FRET (HTRF) assay with a europium-labeled anti-H3K27me3 antibody and streptavidin-labeled XL665 to determine the enzymatic IC50.
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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. EOL-1 (human eosinophilic leukemia) cells are seeded in 6-well plates and treated with varying concentrations of MS-177 (0.01-10 uM) for 16-24 hours. Cells are harvested, lysed, and protein levels of EZH2 and H3K27me3 are analyzed by Western blot using specific antibodies. The DC50 (concentration for 50% degradation) is calculated. For cell viability, cells are treated for 3-5 days, and proliferation is assessed using a CellTiter-Glo luminescent assay. |
| 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. In a patient-derived AML xenograft model, NSG mice are engrafted with primary human AML cells (e.g., MLL-AF9). When the disease is established, MS-177 is administered intraperitoneally (i.p.) at a dose of 30 mg/kg once daily for several weeks. Tumor burden is monitored by measuring human CD45+ cells in the peripheral blood by flow cytometry. At the end of the study, bone marrow and spleen are harvested for EZH2 degradation analysis by Western blot and histopathology. |
| ADME/Pharmacokinetics |
Specific quantitative PK parameters for unconjugated MS-177 are not detailed in the literature. However, as a PROTAC with a molecular weight of 914.02 g/mol, it is expected to have moderate permeability and oral bioavailability, though most studies utilize intraperitoneal (i.p.) administration for in vivo efficacy. Its stability in circulation and ability to penetrate tissues are key properties for its function as a protein degrader.
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| Toxicity/Toxicokinetics |
MS-177 is reported to suppress acute myeloid leukemia growth without apparent toxicity in patient-derived xenograft models at the doses used. However, full toxicological profiles, such as its effect on normal hematopoietic stem cells or potential off-target degradation of other CRBN neo-substrates, are not fully detailed in the available literature. Standard safety endpoints in animal studies include monitoring body weight, general health, and histological analysis of major organs.
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| References | |
| Additional Infomation |
MS-177 is a first-in-class PROTAC degrader for EZH2, representing a paradigm shift from traditional enzyme inhibition to targeted protein degradation. This research-grade chemical overcomes the limitations of catalytic EZH2 inhibitors by destroying the entire protein, thereby disrupting both its canonical PRC2-dependent function and its noncanonical scaffolding functions. As of the latest updates, it is a powerful preclinical research tool and has not yet been approved for clinical use.
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| 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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| SMILES |
CC1=CC(=C(C(=O)N1)CNC(=O)C2=C3C=NN(C3=CC(=C2)C4=CN=C(C=C4)N5CCN(CC5)CCNC(=O)CCOCCNC6=CC=CC7=C6C(=O)N(C7=O)C8CCC(=O)NC8=O)C(C)C)C
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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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