| Size | Price | Stock | Qty |
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| 5mg |
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Purity: =98.97%
GNE-3511 is a novel, highly potent and selective zipper kinase (e.g. DLK, MAP3K12) inhibitor with IC50 of 0.107 uM for DLK. Recently, it was discovered that Dual Leucine Zipper Kinase (DLK, MAP3K12) is an important regulator of neuronal degeneration in various contexts. The phosphorylation of c-Jun was completely suppressed by GNE-3511 at high doses, while at low doses, the proportion of p-c-Jun positive cells was reduced to a moderate level. In an in vitro axon degeneration assay, GNE-3511 prevented primary neurons from degenerating and decreased phosphorylation of the downstream transcription factor c-Jun. GNE-3511 has in vivo plasma clearances that range from moderate (in mice, rats, and cynomolgus) to high (in dogs), moderate volumes of distribution, brief half-lives, and adequate brain penetration to allow testing in animal models of neurodegeneration.
| Targets |
DLK (Ki = 0.5 nM); p-JNK (IC50 = 30 nM); DRG (IC50 = 107 nM); MKK4 (IC50 ＞5000 nM); MKK7 (IC50 ＞5000 nM); JNK1 (IC50 = 129 nM); JNK2 (IC50 = 514 nM); JNK3 (IC50 = 364 nM); MLK1 (IC50 = 67.8 nM); MLK2 (IC50 = 767 nM); MLK3 (IC50 = 602 nM)
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| ln Vitro |
GNE-3511 has a IC50 of 30 nM for p-JNK and 107 nM for DRG, respectively, which indicates inhibitory activity[1].
GNE-3511 has kinase selectivity for MKK4, MKK7, JNK1, JNK2, JNK3, MLK1, MLK2 and MLK3 with IC50 values of ＞5000 nM, ＞5000 nM, 129 nM, 514 nM, 364 nM, 67.8 nM, 767 nM and 602 nM, respectively[1]. GNE-3511 shows concentration-dependent inhibition of neuronal aging in vitro[1]. |
| ln Vivo |
GNE-3511 (oral gavage; 75 mg/kg; single) inhibits DLK in mice to reduce CYP-induced nociceptive behavior[2].
GNE-3511 (oral gavage; 75 mg/kg; single) reduces the edema and bleeding that CYP causes in the mouse bladder[2]. GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg) has moderate plasma clearances in vivo, moderate volumes of distribution, brief half-lives, and moderate brain penetration[2]. |
| Enzyme Assay |
GNE-3511 is a novel, highly potent and selective zipper kinase (e.g. DLK, MAP3K12) inhibitor with IC50 of 0.107 uM for DLK. Recently, it was discovered that Dual Leucine Zipper Kinase (DLK, MAP3K12) is an important regulator of neuronal degeneration in various contexts. The phosphorylation of c-Jun was completely suppressed by GNE-3511 at high doses, while at low doses, the proportion of p-c-Jun positive cells was reduced to a moderate level.
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| Cell Assay |
In each well of 384-well poly-d-lysine coated plates, hek293 cells were seeded with 7500 Dox-inducible human DLK-transfected cells in 40 μL of DMEM with 10% serum. Before adding 5 μL of DMEM containing 60 μM doxycycline, the plates were incubated at 37 °C for 20–24 hours. 5 μL of DLK inhibitors in DMEM were added after the cells had been incubated with doxycycline at 37 °C for roughly 20 h. The cells were then incubated for an additional 5.5 h. at this temperature. Following permeabilization with 0.1% Triton X-100 and blocking for 1 hour with SuperBlock, the cells were then washed with PBS before being incubated with the primary antibodies at 4 °C for the duration of the next day. The secondary antibodies were incubated for 2 hours, followed by a PBS wash and Hoechst 33342 dye staining. Opera Imaging Platform was used to image the cell plates.
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| Animal Protocol |
Cystitis mouse model[1]
75 mg/kg oral gavage;75 mg/kg; single |
| References |
| Molecular Formula |
C23H26F2N6O
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| Molecular Weight |
440.49
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| Exact Mass |
440.21
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| Elemental Analysis |
C, 62.71; H, 5.95; F, 8.63; N, 19.08; O, 3.63
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| CAS # |
1496581-76-0
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
C1CN(CCC1C2=CC(=NC(=C2)N3CCC(C3)(F)F)NC4=NC=CC(=C4)C#N)C5COC5
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| InChi Key |
RHFIAUKMKYHHFA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H26F2N6O/c24-23(25)4-8-31(15-23)22-11-18(17-2-6-30(7-3-17)19-13-32-14-19)10-21(29-22)28-20-9-16(12-26)1-5-27-20/h1,5,9-11,17,19H,2-4,6-8,13-15H2,(H,27,28,29)
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| Chemical Name |
2-[[6-(3,3-difluoropyrrolidin-1-yl)-4-[1-(oxetan-3-yl)piperidin-4-yl]pyridin-2-yl]amino]pyridine-4-carbonitrile
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| Synonyms |
GNE 3511; GNE3511; GNE-3511
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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 |
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 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 | 2.2702 mL | 11.3510 mL | 22.7020 mL | |
| 5 mM | 0.4540 mL | 2.2702 mL | 4.5404 mL | |
| 10 mM | 0.2270 mL | 1.1351 mL | 2.2702 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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