2. Cell Cycle/DNA Damage
  3. Eukaryotic Initiation Factor (eIF)
  4. DNL343

DNL343 is a potent, selective, orally active and brain-penetrant activator of eukaryotic initiation factor eIF2B. DNL343 inhibits the activity of the integrated stress response (ISR) in the central nervous system (CNS) and reverses neurodegeneration and neuroinflammation. DNL343 also prevents motor dysfunction and premature death in eIF2B loss-of-function (LOF) mutant mice. DNL343 can be used in the study of neurodegenerative diseases.

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DNL343 Chemical Structure

DNL343 Chemical Structure

CAS No. : 2278265-85-1

Size Price Stock Quantity
Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO
ready for reconstitution
 USD 453 In-stock
Solution
10 mM * 1 mL in DMSO USD 453 In-stock
Solid
1 mg USD 180 In-stock
5 mg USD 450 In-stock
10 mg USD 750 In-stock
25 mg USD 1500 In-stock
50 mg USD 2450 In-stock
100 mg USD 3980 In-stock
200 mg   Get quote  
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Customer Review

Based on 1 publication(s) in Google Scholar

DNL343 Related Antibodies

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  • Biological Activity

  • Purity & Documentation

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Description

DNL343 is a potent, selective, orally active and brain-penetrant activator of eukaryotic initiation factor eIF2B. DNL343 inhibits the activity of the integrated stress response (ISR) in the central nervous system (CNS) and reverses neurodegeneration and neuroinflammation. DNL343 also prevents motor dysfunction and premature death in eIF2B loss-of-function (LOF) mutant mice. DNL343 can be used in the study of neurodegenerative diseases[1][2][3].

IC50 & Target

eIF2B, integrated stress response (ISR)[1]
In Vitro

DNL343 (0-10 µM; 2 h) inhibits the formation of TDP43(86−414) positive stress granules in H4 cells stressed with sodium arsenite for 2 h in a dose-dependent manner with an IC50 value of 13 nM[2].
DNL343 inhibits hERG with an IC50 value of 3 µM in manual patch clamp assay, but shows a significant right shift in Dofetilide Radioligand Binding Assay with an IC50 value of 15 µM[2].

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

DNL343 Related Antibodies
In Vivo

DNL343 (50 mg/kg; p.o.; once daily for 2 days) inhibits ISR activation in the brain of the Eif 2b5 R191H knock-in mouse model[2].
DNL343 (0-12 mg/kg; i.g.; once daily for 2 or 14 days) inhibits the expression of ISR-dependent transcripts in ONC model mice in a dose-dependent manner[3].
DNL343 (100 mg/kg; mixed in food for 4 weeks) restores normal weight gain in eIF2B LOF mice at the end stage of CNS ISR disease and reduces the elevated expression of ISR transcripts in the brain of eIF2B LOF[3].

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

Animal Model: Acute ISR-driven Neurodegenerative Disease Model of Optic Nerve Compression in Wild-type Mice[3]
Dosage: 0、0.75、3 and 12 mg/kg
Administration: i.g.; ONC is given once three hours after surgery and then once daily for two or fourteen days.
Result: Reduced axonal degeneration at a dose of 12 mg/kg and significantly reduced retinal ganglion cell (RGC) loss at doses of 3 and 12 mg/kg.
Animal Model: 19-26 weeks old eIF2B LOF model mice[3]
Dosage: 100 mg/kg
Administration: The diet containing DNL343 at a concentration of 100 mg/kg was fed for 4 weeks
Result: Blocked ISR activation and reversed ISR activation in mice with advanced disease.
Molecular Weight

457.83

Formula

C20H19ClF3N3O4
CAS No.
Appearance

Solid

Color

White to light yellow

SMILES

ClC(C=C1)=CC=C1OCC(NC23CC(C3)(C4=NN=C([C@@H]5C[C@@H](C5)OC(F)(F)F)O4)C2)=O
Shipping

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

DMSO : 100 mg/mL (218.42 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 2.1842 mL 10.9211 mL 21.8422 mL
5 mM 0.4368 mL 2.1842 mL 4.3684 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, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

  • Molarity Calculator

  • Dilution Calculator

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: ≥ 2.5 mg/mL (5.46 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 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.
  • Protocol 2

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

    Solubility: ≥ 2.5 mg/mL (5.46 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

    Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

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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: 99.94%

COA (247 KB) HNMR (263 KB) LCMS (88 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, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 2.1842 mL 10.9211 mL 21.8422 mL 54.6054 mL
5 mM 0.4368 mL 2.1842 mL 4.3684 mL 10.9211 mL
10 mM 0.2184 mL 1.0921 mL 2.1842 mL 5.4605 mL
15 mM 0.1456 mL 0.7281 mL 1.4561 mL 3.6404 mL
20 mM 0.1092 mL 0.5461 mL 1.0921 mL 2.7303 mL
25 mM 0.0874 mL 0.4368 mL 0.8737 mL 2.1842 mL
30 mM 0.0728 mL 0.3640 mL 0.7281 mL 1.8202 mL
40 mM 0.0546 mL 0.2730 mL 0.5461 mL 1.3651 mL
50 mM 0.0437 mL 0.2184 mL 0.4368 mL 1.0921 mL
60 mM 0.0364 mL 0.1820 mL 0.3640 mL 0.9101 mL
80 mM 0.0273 mL 0.1365 mL 0.2730 mL 0.6826 mL
100 mM 0.0218 mL 0.1092 mL 0.2184 mL 0.5461 mL
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DNL343 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:

DNL3432278265-85-1DNL 343DNL-343Eukaryotic Initiation Factor (eIF)Brain permeabilityAbnormal integrated stress responsecentral nervous systemInhibitorinhibitorinhibit

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