| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
Ki: 0.4 μM[1], 0.56 μM (glyoxalase I)[2]
Glutathione S-transferase P (GSTP / GSTP1-1). TLK117 is a potent and highly specific inhibitor of the GSTP isoenzyme. It binds to the active site with a Ki of 0.4 uM. It also competitively inhibits glyoxalase I (aldolase I) with a Ki of 0.56 uM, linking it to the detoxification of methylglyoxal. |
|---|---|
| ln Vitro |
With a binding affinity greater than GSH and a selectivity for GSTP that is over 50 times greater than that of the GSTM and GSTA classes (Ki=0.4 μM), TLK117 is the most specific GSTP inhibitor found to date[1]. TER 117 is a GST P1-1 isoenzyme inhibitor designed to avoid the known role of GST P1-1 in tumor cells' resistance to drugs. TER 117 is administered as a diethyl ester (TER 117 DEE, also known as TER 199) to aid in its cellular uptake. It has been discovered that TER 117 is a competitive inhibitor of glyoxalase I and GST P1-1[2].
TLK117 is a potent inhibitor of GSTP1-1 with a Ki of 0.4 uM and shows >50-fold selectivity for GSTP over GSTM and GSTA classes. It has a higher binding affinity to GSTP than its natural substrate glutathione (GSH). In cell culture models of fibrosis, it decreases the levels of alpha-SMA, FAS S-glutathionylation, and total protein S-glutathionylation, indicating a reversal of pathological tissue remodeling. |
| ln Vivo |
When the GSTP inhibitor TLK117 is administered orally during the pharyngeal stage of fibrosis, it reduces the amount of remodeling caused by bleomycin and AdTGFβ, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. GSTP activity is significantly reduced four hours after the administration of 50 mg/kg TLK117, and it stays reduced by roughly 60% for at least twenty-four hours[2].
In vivo, TLK117 demonstrates therapeutic efficacy in models of pulmonary fibrosis where fibrosis has already formed. Oral administration (50 mg/kg) substantially reduces GSTP activity within 4 hours, maintaining approximately 60% inhibition for at least 24 hours. It attenuates pathological changes induced by bleomycin or adenoviral TGFbeta (AdTGFbeta), thereby reducing the severity of fibrosis. |
| Enzyme Assay |
Standard GSTP enzyme assays are performed in 96-well plates. Purified recombinant human GSTP1-1 is incubated with the model substrate 1-chloro-2,4-dinitrobenzene (CDNB) and reduced glutathione (GSH). TLK117 is added at increasing concentrations (0.01-10 uM). The conjugation reaction is monitored by the increase in absorbance at 340 nm due to the formation of the thioether product. Ki values are calculated from the competitive inhibition kinetics.
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| Cell Assay |
For cell-based anti-fibrotic assays, primary human lung fibroblasts (e.g., WI-38 or IMR-90) are treated with TGF-beta to induce differentiation into myofibroblasts. TLK117 is added to the culture medium. After 48-72 hours, cells are lysed, and the levels of alpha-smooth muscle actin (alpha-SMA), fibronectin, and collagen I are measured by Western blot. S-glutathionylation levels are assessed by non-reducing SDS-PAGE.
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| Animal Protocol |
For efficacy studies, the bleomycin-induced pulmonary fibrosis model is used in mice. TLK117 is administered orally (50 mg/kg) daily starting after fibrosis has already formed (day 14 post-bleomycin). Lungs are harvested for histology (Ashcroft score), hydroxyproline assay (collagen content), and Western blot for fibrotic markers. GSTP activity is measured in lung homogenates using a fluorogenic substrate to confirm target engagement.
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| ADME/Pharmacokinetics |
TLK117 (TER117) is the active metabolite; it is poorly cell-permeable. Therefore, for in vivo and cellular studies, it is often delivered as a diethyl ester prodrug (TER117 DEE, TER 199) to enhance cellular uptake. Following administration, esterases hydrolyze the prodrug to release active TLK117. It has a molecular weight of 473.54 and is soluble in DMSO. PK studies measure the conversion of prodrug to active drug in plasma.
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| Toxicity/Toxicokinetics |
TLK117 is a research chemical and is not an approved drug. Toxicological data is derived from preclinical studies. It has been studied in clinical trials as the prodrug TLK199 for myelodysplastic syndromes. While generally well-tolerated, adverse events may include reversible liver enzyme elevations, gastrointestinal issues, and fatigue. The safety profile supports its use as a research tool in fibrosis and oncology. Human safety for TLK117 specifically is inferred from TLK199 trials.
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| References |
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| Additional Infomation |
See also: ...View more...
TLK117 is the key active metabolite of Telintra (TLK199). It was developed as an inhibitor of GSTP1-1 to address the role of this enzyme in drug resistance (especially to alkylating agents). Its additional inhibition of glyoxalase I makes it a unique bifunctional molecule. It is currently in research phases for idiopathic pulmonary fibrosis (IPF) and is not commercially approved as a drug. |
| Molecular Formula |
C23H27N3O6S
|
|---|---|
| Molecular Weight |
473.541984796524
|
| Exact Mass |
473.162
|
| CAS # |
152684-53-2
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| Related CAS # |
Ezatiostat;168682-53-9
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| PubChem CID |
444051
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| Appearance |
White to off-white solid powder
|
| LogP |
-0.9
|
| Hydrogen Bond Donor Count |
5
|
| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
13
|
| Heavy Atom Count |
33
|
| Complexity |
665
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
[C@@H](C1C=CC=CC=1)(C(=O)O)NC(=O)[C@H](CSCC1C=CC=CC=1)NC(=O)CC[C@H](N)C(=O)O
|
| InChi Key |
ZPSKWMFLCHMEOY-CMKODMSKSA-N
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| InChi Code |
InChI=1S/C23H27N3O6S/c24-17(22(29)30)11-12-19(27)25-18(14-33-13-15-7-3-1-4-8-15)21(28)26-20(23(31)32)16-9-5-2-6-10-16/h1-10,17-18,20H,11-14,24H2,(H,25,27)(H,26,28)(H,29,30)(H,31,32)/t17-,18-,20+/m0/s1
|
| Chemical Name |
(2S)-2-amino-5-[[(2R)-3-benzylsulfanyl-1-[[(R)-carboxy(phenyl)methyl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
|
| 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: 150 mg/mL (316.76 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.28 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 (5.28 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.28 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 | 2.1118 mL | 10.5588 mL | 21.1175 mL | |
| 5 mM | 0.4224 mL | 2.1118 mL | 4.2235 mL | |
| 10 mM | 0.2112 mL | 1.0559 mL | 2.1118 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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