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Purity: ≥98%
GNE-6776 (GNE6776) is a novel, highly potent, specific, non-covalent, and orally bioavailable USP7 (Ubiquitin specific proteases7) inhibitor with anticancer activity. It is more selective for USP7 (IC50 of ~1.34 uM) than USP47 and USP5 (IC50>200 uM). GNE-6776 can also promote endogenous MDM2 ubiquitination, stabilize p53 and upregulate p21, induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds such as PIM kinase inhibitors; GNE-6776 promotes on-target pathway modulation in human xenografts. Structural studies reveal that GNE-6776 non-covalently targets USP7 12 Å distant from the catalytic cysteine. GNE-6776 attenuates ubiquitin binding and thus inhibits USP7 deubiquitinase activity. It interacts with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain, suggesting that USP7 preferentially interacts with and cleaves ubiquitin moieties that have free Lys48 side chains.
Targets |
USP7
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ln Vitro |
At 15 μM, GNE-6776 significantly inhibits USP7. A highly selective USP7 inhibitor against endogenous cellular deubiquitinases as well as recombinant ones is GNE-6776[1].
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ln Vivo |
GNE-6776 inhibits the growth of EOL-1 xenografts in mice when given orally once or twice a day for ten days at a dose of 100 or 200 mg/kg. [1].
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Animal Protocol |
Immunodeficient C.B-17 SCID mice with an EOL1 AML xenograft, aged 12–16 weeks[1]
100 or 200 mg/kg |
References |
Molecular Formula |
C20H20N4O2
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Molecular Weight |
348.406
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CAS # |
2009273-71-4
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Related CAS # |
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SMILES |
O=C(C1=CC=C(C2=C(CC)C(C3=CC=C(O)C=C3)=C(N)N=C2)C=N1)NC
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InChi Key |
UCYSSYGGXOFJKK-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C20H20N4O2/c1-3-15-16(13-6-9-17(23-10-13)20(26)22-2)11-24-19(21)18(15)12-4-7-14(25)8-5-12/h4-11,25H,3H2,1-2H3,(H2,21,24)(H,22,26)
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Chemical Name |
5-[6-amino-4-ethyl-5-(4-hydroxyphenyl)pyridin-3-yl]-N-methylpyridine-2-carboxamide
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Synonyms |
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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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 : 70~100 mg/mL ( 200.91~287.03 mM )
Ethanol : ~2 mg/mL |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.18 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 (7.18 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 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 (7.18 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 | 2.8702 mL | 14.3509 mL | 28.7018 mL | |
5 mM | 0.5740 mL | 2.8702 mL | 5.7404 mL | |
10 mM | 0.2870 mL | 1.4351 mL | 2.8702 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.
Figure 1: Identification and characterization of USP7 inhibitors.Nature.2017 Oct 26;550(7677):534-538. |
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Figure 2: Selectivity of USP7 inhibitors and synergy with PIM kinase inhibition. Figure 3: USP7 inhibitors compete with ubiquitin binding to USP7.Nature.2017 Oct 26;550(7677):534-538. td> |
Figure 4: USP7 preferentially binds and cleaves ubiquitin moieties with free K48 side chains.Nature.2017 Oct 26;550(7677):534-538. |