DNL343
Based on 1 Customer Validation
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.
For research use only. We do not sell to patients.
- Purity: 99.94%
- CAS No.: 2278265-85-1
- Formula: C20H19ClF3N3O4
- Molecular Weight:457.83
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Storage:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
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Solvent & Solubility
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
eIF2B, integrated stress response (ISR)[1]
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| H4 | IC50 |
12.46 nM
Compound: 32; DNL343
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Neuroprotective activity against NaAsO2-induced human H4 cells expressing GFP TDP43 (86 to 414 residues) assessed as decrease in TDP43 accumulation incubated for 2 hrs by DAPI staining based microscopic analysis
Neuroprotective activity against NaAsO2-induced human H4 cells expressing GFP TDP43 (86 to 414 residues) assessed as decrease in TDP43 accumulation incubated for 2 hrs by DAPI staining based microscopic analysis
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[PMID: 38511649] |
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.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Acute ISR-driven Neurodegenerative Disease Model of Optic Nerve Compression in Wild-type Mice[3]
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Dosage:0、0.75、3 and 12 mg/kg
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Administration:i.g.; ONC is given once three hours after surgery and then once daily for two or fourteen days.
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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.
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Animal Model:19-26 weeks old eIF2B LOF model mice[3]
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Dosage:100 mg/kg
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Administration:The diet containing DNL343 at a concentration of 100 mg/kg was fed for 4 weeks
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Result:Blocked ISR activation and reversed ISR activation in mice with advanced disease.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 2278265-85-1
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Appearance Solid
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Molecular Weight 457.83
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Formula C20H19ClF3N3O4
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Color White to light yellow
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SMILES
ClC(C=C1)=CC=C1OCC(NC23CC(C3)(C4=NN=C([C@@H]5C[C@@H](C5)OC(F)(F)F)O4)C2)=O
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvent & Solubility
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)
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.
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.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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.
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.
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.
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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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
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).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
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
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Data Sheet (273 KB)
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SDS (251 KB)
- English - EN (251 KB)
- Français - FR (251 KB)
- Deutsch - DE (251 KB)
- Norwegian - NO (251 KB)
- Español - ES (251 KB)
- Swedish - SV (251 KB)
- Italian - IT (251 KB)
- Korean - KR (251 KB)
- Portuguese - PT (251 KB)
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Handling Instructions (2659 KB)
References
[2]. Craig R A, et al. Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases[J]. Journal of Medicinal Chemistry, 2024, 67(7): 5758-5782. [Content Brief]
[3]. Yulyaningsih E, et al. DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response[J]. Elife, 2024, 12: RP92173. [Content Brief]
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 |
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| 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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