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| Targets |
The primary target of TTBK1-IN-2 is tau-tubulin kinase 1 (TTBK1), an enzyme that phosphorylates tau and tubulin, contributing to tau aggregation and neurofibrillary tangle formation. By inhibiting TTBK1 activity, the compound reduces pathological tau phosphorylation, offering a promising strategy for modulating tauopathies. The compound shows IC50 values of 0.24 µM and 4.22 µM for TTBK1 inhibition.
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| ln Vitro |
In vitro studies demonstrate that TTBK1-IN-2 is a potent inhibitor of TTBK1 with IC50 values of 0.24 and 4.22 µM. The compound effectively reduces TDP-43 phosphorylation in cell culture models. These studies confirm the compound's ability to inhibit TTBK1-mediated phosphorylation of its substrates, including tau and TDP-43, in cellular systems.
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| ln Vivo |
In vivo studies show that TTBK1-IN-2 reveals good brain penetration and is able to reduce TDP-43 phosphorylation in the spinal cord of transgenic TDP-43 mice. The compound's ability to cross the blood-brain barrier and reach its target in the central nervous system is critical for its potential therapeutic application in neurodegenerative diseases.
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| Enzyme Assay |
Non-cellular enzyme assays for TTBK1-IN-2 typically involve measuring its inhibitory activity against purified TTBK1 enzyme using a kinase assay with a suitable substrate. The compound is incubated with the enzyme and ATP, and phosphorylation of the substrate is measured using radiometric or fluorescence-based methods. IC50 values are determined from dose-response curves. These cell-free systems allow for precise characterization of the compound's inhibitory potency.
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| Cell Assay |
Cellular assays for TTBK1-IN-2 are conducted using neuronal cell lines or primary neurons to assess its effects on tau and TDP-43 phosphorylation. Cells are treated with the compound, and phosphorylation levels are measured by Western blotting using phospho-specific antibodies. Cell viability is assessed to determine cytotoxicity. These studies demonstrate the compound's ability to inhibit TTBK1 activity in a cellular context.
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| Animal Protocol |
In vivo animal experiments for TTBK1-IN-2 typically use transgenic mouse models of TDP-43 proteinopathy. The compound is administered orally or intraperitoneally, and brain and spinal cord tissues are collected for analysis. TDP-43 phosphorylation is assessed by Western blotting or immunohistochemistry. Behavioral and cognitive assessments may be performed to evaluate functional outcomes. These studies evaluate the compound's efficacy in a disease-relevant model.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of TTBK1-IN-2 include good brain penetration in vivo. The compound's ability to cross the blood-brain barrier is essential for its potential use in neurodegenerative diseases. The compound has a molecular weight of 336.78 g/mol and is likely to have favorable lipophilicity for CNS penetration. Further PK parameters such as half-life, oral bioavailability, and plasma protein binding require additional characterization.
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| Toxicity/Toxicokinetics |
Toxicological data for TTBK1-IN-2 are limited, as the compound is a research reagent not intended for human use. Standard laboratory safety precautions should be followed when handling the compound. No significant toxicity has been reported at the doses used in research studies. The compound is for research use only and should not be administered to humans.
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| References |
[1]. Nozal V, et al. TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy. J Med Chem. 2022;65(2):1585-1607.
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| Additional Infomation |
Other information includes TTBK1-IN-2's role as a selective small-molecule inhibitor of TTBK1, an enzyme implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's. TTBK1 phosphorylates tau and tubulin, contributing to tau aggregation and neurofibrillary tangle formation. By inhibiting TTBK1 activity, the compound reduces pathological tau phosphorylation, offering a promising strategy for modulating tauopathies. The compound is used in preclinical studies to explore the role of TTBK1 in neuronal dysfunction, microtubule dynamics, and cognitive decline.
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| Molecular Formula |
C18H13CLN4O
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| Molecular Weight |
336.78
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| Exact Mass |
336.077
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| CAS # |
2765453-51-6
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| PubChem CID |
162679313
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
397
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=CC=C1NC2=NC=NC3=C2C=CN3)OC4=CC=C(C=C4)Cl
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| InChi Key |
RWRSKMSFZCQDMQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H13ClN4O/c19-12-1-5-14(6-2-12)24-15-7-3-13(4-8-15)23-18-16-9-10-20-17(16)21-11-22-18/h1-11H,(H2,20,21,22,23)
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| Chemical Name |
N-[4-(4-chlorophenoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
DMSO: 50 mg/mL (148.46 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline 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 | 2.9693 mL | 14.8465 mL | 29.6930 mL | |
| 5 mM | 0.5939 mL | 2.9693 mL | 5.9386 mL | |
| 10 mM | 0.2969 mL | 1.4846 mL | 2.9693 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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