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| Targets |
PINK1 (PTEN-induced putative kinase 1) and Parkin. T0467 is a signaling activator of the PINK1-Parkin pathway. It promotes the PINK1-dependent recruitment of Parkin from the cytosol to the outer mitochondrial membrane, initiating the mitophagy cascade to remove dysfunctional mitochondria.
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| ln Vitro |
In HeLa/GFP-Parkin cells, T0467 (2.5–20 μM; 3 hours) stimulates GFP-Parkin's mitochondrial translocation over 12 μM[1]. About 21% of HeLa/GFP-Parkin cells exhibit GTP-Parkin translocation to the mitochondria after being exposed to 20 μM T0467 for three hours[1]. In Drosophila, T0467 does not exhibit overt toxicity at concentrations lower than 50 μM. All of the cpds that were investigated lessened the ATP production as well as the defects in mitochondrial morphology and larval locomotion caused by PINK1 inactivation. The mitochondrial Ca2+ response in the muscles of Drosophila larvae was enhanced by T0467 and KTP[1].
In cell-free binding assays, T0467 may interact with components of the PINK1-Parkin signaling cascade. In cellular assays (HeLa cells), T0467 (2.5-20 microM; 3 hours) strongly stimulates the mitochondrial translocation of GFP-Parkin in a concentration-dependent manner. It is inactive in cells lacking PINK1, confirming that its activity is dependent on the PINK1 signaling axis, thus enhancing the cell's ability to clear damaged mitochondria. |
| ln Vivo |
In vivo, T0467 is a potential compound for PINK1-Parkin signaling activation in models of Parkinson's disease and related disorders. Specific in vivo protocols and outcomes are not detailed in the provided search results, but the mechanism suggests that oral or systemic administration could enhance mitophagy, clearing damaged mitochondria in dopaminergic neurons, which are particularly susceptible to mitochondrial dysfunction in PD.
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| Enzyme Assay |
For non-cellular assays, T0467 is not a classical enzyme inhibitor; it is a signaling activator. It can be used in a cell-free system to assess its direct binding to the PINK1 kinase domain using Surface Plasmon Resonance (SPR). Standard enzymology would involve measuring PINK1 kinase activity (phosphorylation of Ubiquitin/ Parkin) in the presence of T0467 using radiolabeled ATP or phospho-specific antibodies (p-Ser65) in a purified protein system.
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| Cell Assay |
For cellular assays, HeLa cells stably expressing GFP-Parkin are seeded in 96-well plates. Cells are treated with T0467 (2.5-20 uM) for 3 hours. Mitophagy is assessed by confocal microscopy to visualize the translocation of GFP-Parkin to the mitochondria (co-stained with MitoTracker). A high-content imaging system can be used to quantify the co-localization. The requirement for PINK1 is validated by using CRISPR-Cas9 generated PINK1-knockout cells, where T0467 should be inactive.
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| Animal Protocol |
For in vivo efficacy, T0467 would likely be administered intraperitoneally or orally to rodent models of Parkinson's disease (e.g., the MPTP mouse model or alpha-synuclein transgenic models). Doses would need to be optimized. Efficacy endpoints would include measurement of dopamine levels in the striatum, quantification of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, and behavioral tests such as the rotarod, open field, and pole tests. Mitophagy markers (e.g., LC3-II accumulation, p62 degradation) would be measured in brain tissue.
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| ADME/Pharmacokinetics |
T0467 is a small molecule with a molecular weight of 441.49 g/mol and a molecular formula of C24H26F3N5. It is soluble in DMSO for in vitro preparation. Detailed pharmacokinetic parameters (half-life, Cmax, AUC) are not extensively published in the provided excerpts. It should be stored at -20degC for long-term stability. It is noted for its chemical stability and ability to activate parkin translocation without inducing the accumulation of PINK1 itself.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for T0467 are not provided in the search results. It is a research compound and is not intended for human use. Standard safety precautions should be followed. As a potential mitophagy activator, there is a theoretical risk of over-activating autophagy, which could lead to unwanted cell death in non-target cells if not properly regulated. However, the PINK1-dependency may confer a degree of selectivity to damaged mitochondria. No acute toxicity is reported in the summary.
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| References | |
| Additional Infomation |
N-[2-(3,5-difluorophenyl)ethyl]-4-(2-fluoro-5-{[(2S)-2-methylpiperazin-1-yl]methyl}phenyl)pyrimidin-2-amine is an organic molecular entity.
T0467 is a research-grade chemical tool used to study the PINK1-Parkin pathway. It is distinct from the typical mitochondrial-targeted antioxidants or general autophagy inducers as it specifically activates the upstream signaling in the mitophagy cascade. It is not an FDA-approved drug. It is used in preclinical research to validate that enhancing mitophagy is a viable therapeutic strategy for Parkinson's disease (PD). |
| Molecular Formula |
C24H26F3N5
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| Molecular Weight |
441.49
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| Exact Mass |
441.214
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| CAS # |
859518-94-8
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| PubChem CID |
58603496
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| Appearance |
Off-white to light brown solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
32
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| Complexity |
560
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N1CCN(CC2C=C(C(=CC=2)F)C2=NC(NCCC3=CC(F)=CC(=C3)F)=NC=C2)[C@@H](C)C1
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| InChi Key |
GNYKYGZGDGZPOK-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C24H26F3N5/c1-16-14-28-8-9-32(16)15-18-2-3-22(27)21(12-18)23-5-7-30-24(31-23)29-6-4-17-10-19(25)13-20(26)11-17/h2-3,5,7,10-13,16,28H,4,6,8-9,14-15H2,1H3,(H,29,30,31)/t16-/m0/s1
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| Chemical Name |
N-[2-(3,5-difluorophenyl)ethyl]-4-[2-fluoro-5-[[(2S)-2-methylpiperazin-1-yl]methyl]phenyl]pyrimidin-2-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 |
| 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: 33.33 mg/mL (75.49 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.66 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2651 mL | 11.3253 mL | 22.6506 mL | |
| 5 mM | 0.4530 mL | 2.2651 mL | 4.5301 mL | |
| 10 mM | 0.2265 mL | 1.1325 mL | 2.2651 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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