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MAK-683 (MAK683; extracted from patent US20160176882 A1, compound example 2) is a novel and potent embryonic ectoderm development protein (EED) inhibitor and allosteric inhibitor of polycomb repressive complex 2 (PRC2) with potential anticancer activity. It inhibits EED and PRC2 with IC50s of 59, 89, 26 nM in EED Alphascreen binding, LC-MS and ELISA assay.
| ln Vitro |
After 14 days of therapy, MAK683 has an IC50 of 30 nM against B-cell lymphoma cells KARPAS422 that exhibits anti-proliferative action [1].
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| References | |
| Additional Infomation |
EED Inhibitor MAK683 is an inhibitor of embryonic ectoderm development protein (EED) and allosteric inhibitor of polycomb repressive complex 2 (PRC2), with potential antineoplastic activity. Upon administration, MAK683 selectively binds to the domain of EED that interacts with trimethylated lysine 27 on histone 3 (H3K27me3), which leads to a conformational change in the EED H3K27me3-binding pocket and prevents the interaction of EED with the histone methyltransferase enhancer zeste homolog 2 (EZH2). Disruption of the EED-EZH2 protein-protein interaction (PPI) results in a loss of H3K27me3-stimulated PRC2 activity and prevents H3K27 trimethylation. This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased tumor cell proliferation in EZH2-mutated and PRC2-dependent cancer cells. PRC2, a histone H3 lysine 27 methyltransferase and multi-protein complex comprised of EZH2, EED and suppressor of zeste 12 (SUZ12), plays a key role in gene regulation, especially during embryonic development. EZH2, the catalytic subunit of PRC2, is overexpressed or mutated in a variety of cancer cells. EED is essential for the histone methyltransferase activity of PRC2 because EED directly binds to H3K27me3.
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| Molecular Formula |
C20H17FN6O
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|---|---|
| Molecular Weight |
376.386986494064
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| Exact Mass |
376.144
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| CAS # |
1951408-58-4
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| Related CAS # |
MAK683 hydrochloride;2170606-94-5
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| PubChem CID |
121412508
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| Appearance |
White to off-white solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
541
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C=CC2=C(C=1CNC1=NC=C(C3=CC=CN=C3C)C3=NN=CN13)CCO2
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| InChi Key |
XLIBABIFOBYHSV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H17FN6O/c1-12-13(3-2-7-22-12)16-10-24-20(27-11-25-26-19(16)27)23-9-15-14-6-8-28-18(14)5-4-17(15)21/h2-5,7,10-11H,6,8-9H2,1H3,(H,23,24)
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| Chemical Name |
N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine
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| Synonyms |
MAK683 MAK 683 MAK-683 EED inhibitor-1 EED inhibitor 1 EED inhibitor1
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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 : ~40 mg/mL (~106.27 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.17 mg/mL (5.77 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 21.7 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: ≥ 2.17 mg/mL (5.77 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 21.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6568 mL | 13.2841 mL | 26.5682 mL | |
| 5 mM | 0.5314 mL | 2.6568 mL | 5.3136 mL | |
| 10 mM | 0.2657 mL | 1.3284 mL | 2.6568 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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