2. MAPK/ERK Pathway
  3. MAP3K
  4. GNE-3511

GNE-3511 is an orally active bioavailable and brain-penetrant dual leucine zipper kinase (DLK) inhibitor with a Ki of 0.5 nM. GNE-3511 can cross the blood-brain-barrier and can be used for the research of neurodegenerative diseases.

For research use only. We do not sell to patients.

CAS No. : 1496581-76-0

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Based on 11 publication(s) in Google Scholar

GNE-3511 Related Antibodies

Top Publications Citing Use of Products

    GNE-3511 purchased from MedChemExpress. Usage Cited in: Cell Rep. 2019 Sep 3;28(10):2581-2593.e5.  [Abstract]

    Representative images of the NMJ synaptic terminal at muscle 4 in third-instar wild-type and hiw mutant larvae raised on food treated with either DMSO (vehicle control) or DLK inhibitor (DLKi) (GNE-3511) (35 µM). NMJs were stained for the presynaptic bouton marker DVGLUT (green) and nerve membrane marker HRP (red). Scale bar: 50 μm.

    GNE-3511 purchased from MedChemExpress. Usage Cited in: Cell Rep. 2019 Sep 3;28(10):2581-2593.e5.  [Abstract]

    Representative images of the NMJ synaptic terminal at muscle 4 in third-instar wild-type and dFmr1 mutant larvae raised on food treated with either DMSO (vehicle control) or DLK inhibitor (GNE-3511) (35 μM). Representative bouton images are shown in the inset panels to the right of the respective genotype. Scale bar: 25 μm.

    GNE-3511 purchased from MedChemExpress. Usage Cited in: Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):E9899-E9908.  [Abstract]

    Low-throughput manual replating assay with the top screen hit 17AAG (1 µM), a structurally different HSP90 inhibitor (15 nM GT), and 500 nM DLK inhibitor GNE-3511 (DLKi) (24 h).

    GNE-3511 purchased from MedChemExpress. Usage Cited in: Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):E9899-E9908.  [Abstract]

    Adult DRG neurons plated and treated with DMSO, 1 µM 17AAG, and 500 nM DLKi (GNE-3511). At 24 h postinjury (hpi), adult DRG neurons were fixed and immunostained for proregenerative markers (gray in Top and red in merged) and neuronal Tuj1 (green).

    GNE-3511 purchased from MedChemExpress. Usage Cited in: Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):E9899-E9908.  [Abstract]

    Adult DRG neurons were dissociated, plated, and treated with 1 µM 17AAG, 500 nM DLKi (GNE-3511) (24 h), or DMSO. At 24 hpi, RNA was collected, and RAGs were analyzed via qRT-PCR.

    View All MAP3K Isoform Specific Products:

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    MAP3K7/TAK1 MAP3K8/COT/Tpl2 MAP3K6/ASK2 MAP3K5/ASK1 MAP3K12/DLK/Pref-1 NIK/MAP3K14

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    Description

    GNE-3511 is an orally active bioavailable and brain-penetrant dual leucine zipper kinase (DLK) inhibitor with a Ki of 0.5 nM. GNE-3511 can cross the blood-brain-barrier and can be used for the research of neurodegenerative diseases[1].

    IC50 & Target

    Ki: 0.5 nM (DLK); IC50: 30 nM (p-JNK), 107 nM (DRG); ＞5000 nM (MKK4), ＞5000 nM (MKK7), 129 nM (JNK1),514 nM (JNK2), 364 nM (JNK3), 67.8 nM (MLK1), 767 nM (MLK2) and 602 nM (MLK3)[1]
    Cellular Effect
    Cell Line Type Value Description References
    HEK293 IC50
    30 nM
    Compound: 26, GNE-3511
    Inhibition of human DLK transfected in HEK293 cells assessed as JNK phosphorylation after 5.5 hrs by Hoechst-33342 staining-based assay
    Inhibition of human DLK transfected in HEK293 cells assessed as JNK phosphorylation after 5.5 hrs by Hoechst-33342 staining-based assay
    		[PMID: 25341110]
    In Vitro

    GNE-3511 has inhibitory activity for p-JNK and DRG with IC50 values of 30 nM and 107 nM, respectively[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 displays concentration-dependent protection of neurons from degeneration in vitro[1].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    GNE-3511 Related Antibodies
    In Vivo

    GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced nociceptive behavior by inhibiting DLK in mice[2].
    GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced edema and hemorrhage in mouse bladder[2].
    GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg) exhibits moderate in vivo plasma clearances, moderate volumes of distribution, short half-lives, and brain penetration[2].
    Pharmacokinetic Parameters of GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg)[2].

    species CLp (mL/min/kg Vdss (L/kg t1/2 (h) F (%) Bu/Pu CSF/Pu
    mouse 56 2.5 0.6 45 0.24 at 6 h
    rat 30 3.7 1.8 63 0.7 0.4
    dog 41 6.5 4 32 0.4
    cynomolgous 16 3.1 2.4 19 0.6

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Model: Cystitis mouse model[1]
    Dosage: 75 mg/kg
    Administration: oral gavage;75 mg/kg; single
    Result: Significantly reduced the number of nociceptive behavior as well as nociceptive score.
    Had no impact on bladder weight, did not induce bladder edema or hemorrhage and significantly suppressed CYP-induced increase in bladder weight, bladder edema, and hemorrhage.
    Animal Model: mouse, rat, cynomolgus and dog[2]
    Dosage: 1 mg/k, 5 mg/kg
    Administration: iv.; 1 mg/kg or po.; 5 mg/kg
    Result: Exhibited moderate in vivo plasma clearances, moderate volumes of distribution, short half-lives and brain penetration.
    Molecular Weight

    440.49

    Formula

    C23H26F2N6O
    CAS No.
    Appearance

    Solid

    Color

    Light yellow to yellow

    SMILES

    N#CC1=CC=NC(NC2=NC(N3CC(F)(F)CC3)=CC(C4CCN(C5COC5)CC4)=C2)=C1
    Shipping

    Room temperature in continental US; may vary elsewhere.
    Storage
    Powder -20°C 3 years
    4°C 2 years
    In solvent -80°C 1 year
    -20°C 6 months
    Solvent & Solubility
    In Vitro: 

    DMSO : 31.25 mg/mL (70.94 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

    Preparing
    Stock Solutions
    Concentration Solvent Mass 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
    View the Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 1 year; -20°C, 6 months. When stored at -80°C, please use it within 1 year. When stored at -20°C, please use it within 6 months.

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    Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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    Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

    This equation is commonly abbreviated as: C1V1 = C2V2

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    In Vivo:

    Select the appropriate dissolution method based on your experimental animal and administration route.

    For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
    To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
    The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

    • Protocol 1

      Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

      Solubility: ≥ 2.08 mg/mL (4.72 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (20.8 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

      Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
    In Vivo Dissolution Calculator
    Please enter the basic information of animal experiments:

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    Number of animals

    Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
    Please enter your animal formula composition:
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    Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
    The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
    Calculation results:
    Working solution concentration: mg/mL
    Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
    The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
    Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
     If the continuous dosing period exceeds half a month, please choose this protocol carefully.
    Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
    Purity & Documentation

    Purity: 99.54%

    SDS (393 KB)

    COA (248 KB) HNMR (144 KB) RP-HPLC (170 KB) LCMS (110 KB)

    Handling Instructions (2659 KB)
    References

    Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 1 year; -20°C, 6 months. When stored at -80°C, please use it within 1 year. When stored at -20°C, please use it within 6 months.

    Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
    DMSO 1 mM 2.2702 mL 11.3510 mL 22.7020 mL 56.7550 mL
    5 mM 0.4540 mL 2.2702 mL 4.5404 mL 11.3510 mL
    10 mM 0.2270 mL 1.1351 mL 2.2702 mL 5.6755 mL
    15 mM 0.1513 mL 0.7567 mL 1.5135 mL 3.7837 mL
    20 mM 0.1135 mL 0.5675 mL 1.1351 mL 2.8377 mL
    25 mM 0.0908 mL 0.4540 mL 0.9081 mL 2.2702 mL
    30 mM 0.0757 mL 0.3784 mL 0.7567 mL 1.8918 mL
    40 mM 0.0568 mL 0.2838 mL 0.5675 mL 1.4189 mL
    50 mM 0.0454 mL 0.2270 mL 0.4540 mL 1.1351 mL
    60 mM 0.0378 mL 0.1892 mL 0.3784 mL 0.9459 mL
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    GNE-3511 Related Classifications

    Help & FAQs
    • Do most proteins show cross-species activity?

      Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

    Keywords:

    GNE-35111496581-76-0GNE3511GNE 3511MAP3KMAP kinase kinase kinase, MEKK, MAPKKKoralbrain-penetrantdual leucine zipper kinase (DLK)blood-brain-barrierneurodegenerative diseasesInhibitorinhibitorinhibit

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