| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg | |||
| Other Sizes |
| Targets |
T-448 targets lysine-specific demethylase 1 (LSD1). LSD1 is a histone demethylase that specifically removes methyl groups from histone H3 at lysine 4 (H3K4) and lysine 9 (H3K9). By irreversibly inhibiting LSD1, T-448 increases the methylation of H3K4, which is associated with active gene transcription.
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| ln Vitro |
T-448 elevates H3K4 methylation levels, increases the mRNA expression of neuroplasticity-related genes (including brain-derived neurotrophic factor (Bdnf)), and improves learning deficits [1]. Reverse transcription polymerase chain reaction[1].
In vitro, T-448 inhibits LSD1 enzyme activity with an IC50 of 22 nM. It enhances H3K4 methylation in primary cultured rat neurons. This indicates that the compound is a potent and effective LSD1 inhibitor that can modulate histone methylation in cells. |
| ln Vivo |
T-448 has negligible impact on the LSD1-GFI1B complex and has great hematological safety in mice by creating compact formyl-FAD adducts. T-448 promotes brain H3K4 methylation and partially improves learning ability in mice with NMDA receptor hypofunction [1]. T-448 enhances H3K4 methylation in the brain without eliciting hematological adverse effects even at levels of 100 mg/kg [1].
In vivo, T-448 has been shown to increase brain H3K4 methylation and partially restore learning function in mice with NMDA receptor hypofunction. It improves learning function without causing thrombocytopenia, a side effect often associated with LSD1 inhibitors. This suggests it has a unique therapeutic approach for central nervous system disorders. |
| Enzyme Assay |
The inhibitory activity of T-448 on LSD1 is typically measured in a cell-free enzyme assay. Recombinant LSD1 is incubated with a histone H3 peptide substrate and varying concentrations of T-448. The demethylation activity is measured, and the IC50 is calculated from the concentration-response curve.
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| Cell Assay |
RT-PCR[1].
Cell Types: Primary cultured rat neurons. Tested Concentrations: 0-10μM. Incubation period: 1 day of treatment. Experimental Results: Ucp2 H3K4me2 and Ucp2 mRNA were Dramatically increased. Cellular assays are performed using primary cultured rat neurons. Neurons are treated with T-448, and the levels of H3K4 methylation are measured by Western blot using a specific antibody. The compound's effects on gene expression can also be assessed by qPCR. |
| Animal Protocol |
Animal/Disease Models: NR1-hypo mouse[1].
Doses: 1. 10 mg/kg. Doses: po (po (oral gavage)) 3 weeks. Experimental Results: H3K4me2 levels around the Bdnf, Arc, and Fos genes increased in a dose-dependent manner in the mouse hippocampus. The results were a partial but statistically significant and dose-dependent rescue of correct choice rates in NR1-hypo mice. In vivo efficacy is evaluated in mouse models of memory deficits, such as those with NMDA receptor hypofunction. T-448 is administered orally, and its effects on learning and memory are assessed using behavioral tests like the Morris water maze or novel object recognition. Brain H3K4 methylation levels are also measured. |
| ADME/Pharmacokinetics |
T-448 has a molecular weight of 386.50 g/mol. As a small molecule, it is orally active. Its pharmacokinetic properties, such as oral bioavailability, half-life, and brain penetration, would be determined in preclinical studies. Its ability to cross the blood-brain barrier is key to its efficacy in CNS disorders.
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| Toxicity/Toxicokinetics |
T-448 is generally well-tolerated in preclinical studies. It improves learning function without causing thrombocytopenia, suggesting it has a better safety profile than some other LSD1 inhibitors. Its toxicity is related to its on-target effects on gene expression.
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| References | |
| Additional Infomation |
T-448 is a novel, orally active, and irreversible LSD1 inhibitor with an IC50 of 22 nM. It shows unique therapeutic approaches for central nervous system disorders associated with epigenetic dysregulation and is a valuable tool for studying the role of LSD1 in learning and memory.
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| Molecular Formula |
C21H24N4O5S
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|---|---|
| Molecular Weight |
444.5041
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| Exact Mass |
444.146
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| CAS # |
1597426-53-3
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| Related CAS # |
T-448 free base;1597426-52-2
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| PubChem CID |
167994955
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
31
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| Complexity |
563
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(C([H])([H])[H])=NN=C1N([H])C(C1=C([H])C([H])=C([H])C(=C1[H])[C@@]1([H])C([H])([H])[C@]1([H])N([H])C1([H])C([H])([H])C([H])([H])C1([H])[H])=O.O([H])C(/C(/[H])=C(\[H])/C(=O)O[H])=O
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| InChi Key |
BNLKYWVPJPFTMA-WLHGVMLRSA-N
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| InChi Code |
InChI=1S/C17H20N4OS.C4H4O4/c1-10-20-21-17(23-10)19-16(22)12-5-2-4-11(8-12)14-9-15(14)18-13-6-3-7-13;5-3(6)1-2-4(7)8/h2,4-5,8,13-15,18H,3,6-7,9H2,1H3,(H,19,21,22);1-2H,(H,5,6)(H,7,8)/b;2-1+
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| Chemical Name |
(E)-but-2-enedioic acid;3-[2-(cyclobutylamino)cyclopropyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide
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| Synonyms |
T-448 T448 T 448
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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: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~16.67 mg/mL (~43.13 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (4.32 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 16.7 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: ≥ 1.67 mg/mL (4.32 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 16.7 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. View More
Solubility in Formulation 3: ≥ 1.67 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2497 mL | 11.2486 mL | 22.4972 mL | |
| 5 mM | 0.4499 mL | 2.2497 mL | 4.4994 mL | |
| 10 mM | 0.2250 mL | 1.1249 mL | 2.2497 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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