GNE-781

Alias: GNE781; GNE 781; GNE-781.
Cat No.:V4553 Purity: ≥98%
GNE-781 (GNE781) is a novel, highly potent and selectiveinhibitor of CBP (Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein) with immunomodulatory and anticancer effects.
GNE-781 Chemical Structure CAS No.: 1936422-33-1
Product category: Epigenetic Reader Domain
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

GNE-781 (GNE781) is a novel, highly potent and selective inhibitor of CBP (Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein) with immunomodulatory and anticancer effects. It inhibits CBP with an IC50 of 0.94 nM in TR-FRET assay. GNE-781 also inhibits BRET and BRD4(1) with IC50s of 6.2 nM and 5100 nM, respectively. GNE-781 showed TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM, BRD4(1) IC50 = 5,100 nΜ) that maintained good in vivo PK properties in multiple species. GNE-781 displays anti-tumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.

Biological Activity I Assay Protocols (From Reference)
Targets

IC50: 0.94 nM (CBP), 6.2 nM (BRET), 5100 nΜ (BRD4(1))[1]

ln Vitro
GNE-781 is a highly developed, strong, and specific bromodomain inhibitor of the CBP (cyclic adenosine monophosphate response element-binding protein). The transcript levels of FOXP3 (forkhead box P3) are decreased by GNE-781. Analysis of a subset of bromodomains revealed that GNE-781 has significant selectivity for both CBP (5425-fold) and P300 (4250-fold), and is very selective for CBP/P300. GNE-781 exhibits cellular potency and selectivity in the ideal ratio—5425 times higher than BRD4 (1)—[1].
ln Vivo
In mice bearing MOLM-16 AML xenografts, GNE-781 (3-30 mg/kg; po; twice daily for 21 days) suppresses tumor growth inhibition (%TGI) at doses of 3, 10, and 30 mg/kg 73%, 71%, and 89%, respectively [1]. Foxp3 transcript levels are lowered in a dose-dependent manner by GNE-781. At doses as low as 3 mg/kg, GNE-781 (3-30 mg/kg) inhibits MYC at 2 and 8 hours; at 10 and 30 mg/kg, the greatest inhibition (87% and 88% inhibition) is reached at 2 hours [1].
Animal Protocol
Mice[1] Twelve female CD-1 mice are used. All animals are 6-9 weeks old at the time of study and weighed between 20 and 35 g. Animals (n=3 per dosing route) are dosed with 10 or GNE-781 at 1 mg/kg iv (in propyl ethylene glycol 400 (35% v/v) and water (65% v/v)) or 5 mg/kg po (suspended in 0.5% w/v methylcellulose, 0.2% w/v Tween 80). Food and water are available ad libitum to all animals. Serial blood samples (15 μL) are collected by tail nick at 0.033, 0.083, 0.25, 0.5, 1, 3, 8, and 24 h after the intravenous administration and 0.083, 0.25, 0.5, 1, 3, 8, and 24 h after the oral administration. All blood samples are diluted with 60 μL of water containing 1.7 mg/mL EDTA and kept at -80 °C until analysis[1]. Rats[1] Twelve male Sprague-Dawley rats are used. All animals are 6-9 weeks old at the time of study and weighed between 200 and 300 g. Animals (n=3 per dosing route) are dosed with 10 or GNE-781 at 1 mg/kg iv (in propyl ethylene glycol 400 (35% v/v) and water (65% v/v)) or 5 mg/kg po (suspended in 0.5% w/v methylcellulose, 0.2% w/v Tween 80). Food and water are available ad libitum to animals in the iv groups. Animals in po groups are fasted overnight and food withheld until 4 h postdose. Approximately 250 μL of blood are collected via the catheter at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after the intravenous or oral administration. All blood samples are collected into tubes containing 5 μL of 0.5 M K2EDTA and processed for plasma. Samples are centrifuged (2500g for 15 min at 4°C) within 1 h of collection, and plasma samples are kept at -80 °C until analysis[1].
References
[1]. Romero FA, et al. GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP). J Med Chem. 2017 Nov 22;60(22):9162-9183
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C27H33F2N7O2
Molecular Weight
525.593432188034
CAS #
1936422-33-1
SMILES
O=C(N1CCC(N(C2CCOCC2)N=C3N4CCCC5=C4C=C(C(F)F)C(C6=CN(C)N=C6)=C5)=C3C1)NC
InChi Key
CQCWHSDMJBAGDC-UHFFFAOYSA-N
InChi Code
InChI=1S/C27H33F2N7O2/c1-30-27(37)34-9-5-23-22(16-34)26(32-36(23)19-6-10-38-11-7-19)35-8-3-4-17-12-20(18-14-31-33(2)15-18)21(25(28)29)13-24(17)35/h12-15,19,25H,3-11,16H2,1-2H3,(H,30,37)
Chemical Name
3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide
Synonyms
GNE781; GNE 781; GNE-781.
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)
Solubility Data
Solubility (In Vitro)
DMSO : ~100 mg/mL (~190.26 mM)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.9026 mL 9.5131 mL 19.0262 mL
5 mM 0.3805 mL 1.9026 mL 3.8052 mL
10 mM 0.1903 mL 0.9513 mL 1.9026 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.

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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.

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