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| 5mg |
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| 50mg |
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| Targets |
MK6-83 specifically targets the TRPML1 channel (also known as mucolipin 1), a member of the transient receptor potential (TRP) family of ion channels. TRPML1 is a calcium-permeable channel that resides on the membranes of lysosomes and late endosomes. It is responsible for releasing calcium ions from the lysosomal lumen into the cytosol, a process that is essential for various lysosomal functions, including membrane trafficking, lysosomal acidification, and fusion events. By acting as a potent agonist, MK6-83 binds to the TRPML1 channel and promotes its opening, thereby increasing the release of calcium from lysosomes. This calcium signaling is crucial for restoring lysosomal function, particularly in cells where TRPML1 activity is compromised due to genetic mutations. MK6-83 shows moderate selectivity for TRPML1 over the related channels TRPML2 and TRPML3, and it is also known to activate certain mutant variants of the channel, such as F465L and F408D, while having weaker effects on other mutants like R403C or V446L.
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| ln Vitro |
MK6-83 does not show enough cytotoxicity between 0.2 and 30 μM [1]. When it comes to fibroblast lysosomes isolated from cells expressing R403C or V446L, MK6-83 seems to be much more powerful than when it comes to cells isolated from TRPML1 −/− cells [1].
In vitro studies have confirmed that MK6-83 is a potent and efficacious activator of TRPML1. The compound has demonstrated the ability to activate both wild-type and specific mutant variants of the TRPML1 channel. Importantly, MK6-83 has been shown to be effective in restoring lysosomal function in fibroblasts from MLIV patients. For example, in cells expressing the R403C or V446L mutations, treatment with 0-10 μM MK6-83 for 24 hours showed efficacy in restoring lysosomal function, as measured by the normalization of lysosomal pH, calcium levels, and membrane trafficking. The compound does not show significant cytotoxicity at concentrations ranging from 0.2 to 30 μM, a crucial feature for its potential therapeutic application. These in vitro findings provide strong evidence for the compound's mechanism of action and its potential to correct the cellular pathology of MLIV. |
| ln Vivo |
In vivo studies for MK6-83 are limited, as it is primarily used as a research tool for studying TRPML1 function and MLIV. Its primary value lies in its ability to activate TRPML1 and restore lysosomal function in cell-based models of the disease. As a potential therapeutic for MLIV, further in vivo studies in animal models of the disease would be necessary to evaluate its efficacy and safety. However, detailed in vivo efficacy data have not been published.
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| Enzyme Assay |
The in vitro assays for MK6-83 are primarily functional, focusing on its ability to activate the TRPML1 channel. These assays are typically conducted in cell lines that heterologously express TRPML1, such as HEK293 cells. The channel's activity is measured using calcium imaging, where cells are loaded with a calcium-sensitive fluorescent dye, and the increase in intracellular calcium concentration is monitored upon the addition of MK6-83. This provides a direct measure of the compound's agonistic activity. The potency and efficacy of MK6-83 are determined by generating dose-response curves. Additionally, the compound's ability to restore lysosomal function can be assessed by measuring lysosomal pH or the accumulation of lipids in patient-derived fibroblasts.
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| Cell Assay |
Cell viability assay[1].
Cell Types: Lysosomes isolated from fibroblast cell lines of MLIV patients carrying F408D, R403C or V446L mutations[1]. Tested Concentrations: 0-10μM. Incubation Duration: 24 hrs (hours). Experimental Results: Effective on fibroblast lysosomes isolated from R403C or V446L expressing cells. There was no significant effect on lysosomes isolated from TRPML1-/- fibroblasts. Cellular assays for MK6-83 are crucial for evaluating its ability to rescue the MLIV phenotype. These assays are performed using fibroblasts derived from MLIV patients that harbor specific mutations in the MCOLN1 gene. Cells are treated with MK6-83, and the restoration of lysosomal function is assessed. Key readouts include the normalization of lysosomal pH, the reduction of lysosomal storage material (such as lipids or glycosaminoglycans), and the restoration of normal membrane trafficking. The compound's cytotoxicity is also carefully evaluated in these assays. These cell-based experiments are essential for demonstrating the therapeutic potential of MK6-83 and for understanding its mechanism of action in a disease-relevant context. |
| Animal Protocol |
In vivo animal experiments for MK6-83 are not well-documented. As a research compound, its primary use is in cellular and biochemical assays to study the biology of TRPML1 and the pathophysiology of MLIV. While animal models of MLIV exist, such as the Mcoln1 knockout mouse, detailed studies using MK6-83 in these models have not been published.
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| ADME/Pharmacokinetics |
MK6-83 has a molecular weight of 336.47 g/mol and a molecular formula of C16H20N2O2S2. It is a small molecule that is typically soluble in DMSO. For storage, it is recommended to be kept at -20°C. The compound is available as a research-grade reagent.
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| Toxicity/Toxicokinetics |
The toxicity profile of MK6-83 has been assessed in vitro, where it does not show significant cytotoxicity at concentrations between 0.2 and 30 μM. As a research compound, comprehensive toxicological evaluations, including genotoxicity, cardiotoxicity, and long-term safety studies, have not been extensively published. Its safety for in vivo use has not been established.
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| References | |
| Additional Infomation |
MK6-83 is a research compound that functions as a potent agonist of the TRPML1 calcium channel. It is a promising candidate for the study of mucolipidosis type IV (MLIV), a rare and devastating lysosomal storage disorder. By activating TRPML1, MK6-83 aims to restore lysosomal function in cells with MLIV-causing mutations. Although it has not yet entered clinical trials, MK6-83 serves as a valuable tool for understanding TRPML1 biology and for developing potential therapies for MLIV and other lysosomal disorders.
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| Molecular Formula |
C16H20N2O2S2
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|---|---|
| Molecular Weight |
336.46
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| Exact Mass |
336.096
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| CAS # |
1062271-24-2
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| PubChem CID |
18191179
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
502.6±60.0 °C at 760 mmHg
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| Flash Point |
257.8±32.9 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.633
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
22
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| Complexity |
457
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
IRGYSXZCDAWOOC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H20N2O2S2/c1-13-9-10-16(21-13)22(19,20)17-14-7-3-4-8-15(14)18-11-5-2-6-12-18/h3-4,7-10,17H,2,5-6,11-12H2,1H3
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| Chemical Name |
5-methyl-N-(2-piperidin-1-ylphenyl)thiophene-2-sulfonamide
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| Synonyms |
MK683; MK6 83; MK6-83
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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 : ~25 mg/mL (~74.30 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.43 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 (7.43 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9721 mL | 14.8606 mL | 29.7212 mL | |
| 5 mM | 0.5944 mL | 2.9721 mL | 5.9442 mL | |
| 10 mM | 0.2972 mL | 1.4861 mL | 2.9721 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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