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| 10mg |
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| Targets |
MRT68921 targets the autophagy-related kinases ULK1 and ULK2. ULK1 is a serine/threonine protein kinase that acts as a key initiator of autophagy, a critical cellular degradation and recycling pathway. ULK2 is a highly similar homolog that shares overlapping functions. By potently inhibiting both kinases, MRT68921 effectively blocks the autophagic process at its very first step. This makes it a crucial tool for studying the ULK1/2-dependent functions of autophagy, distinguishing them from other cellular processes.
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| ln Vitro |
ULK1 is a serine/threonine protein kinase that is necessary for autophagy's early phases. MRT68921 prevents autophagy in cells and inhibits ULK1 and ULK2 in vitro. The most effective inhibitor of ULK1 and ULK2, MRT68921, reduces the IC50 for both ULK1 (2.9 nm) and ULK2 (1.1 nm) by more than 15 and 30 times, respectively. This compound's particular capacity to suppress autophagy is made possible by ULK1. ULK1 may be involved in the maturation and initiation of autophagosomes, as evidenced by the buildup of stalled early autophagosome structures upon ULK1 inhibition [1].
In vitro, MRT68921 demonstrates exceptional potency against its targets. It inhibits ULK1 with an IC₅₀ of 2.9 nM and ULK2 with an IC₅₀ of 1.1 nM. This potent inhibition translates to effective blockade of autophagy in cellular models. For example, in mouse embryonic fibroblasts, treatment with MRT68921 blocks autophagy, causing an accumulation of stalled early autophagosomal structures. The compound's high potency and selectivity make it a superior tool compared to other, less specific autophagy inhibitors, allowing for more precise dissection of ULK1/2's role in autophagy. |
| ln Vivo |
In vivo data for MRT68921 are not as extensively reported as its in vitro profile. However, given its potent activity as a ULK1/2 inhibitor, it holds significant promise for in vivo studies aimed at validating autophagy as a therapeutic target in diseases like cancer. Its ability to potently block autophagy in cells provides a strong rationale for its application in animal models. Further studies are required to fully characterize its pharmacokinetic properties and in vivo efficacy in various disease models.
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| Enzyme Assay |
In vitro kinase assays for MRT68921 are typically performed using recombinant ULK1 and ULK2 enzymes. The compound is dissolved in DMSO and serially diluted in assay buffer. The reaction is initiated by adding ATP and a specific peptide substrate. Following incubation at 30°C, the phosphorylated product is quantified using methods like fluorescence polarization, AlphaScreen, or radioactive ATP incorporation. IC₅₀ values are determined from dose-response curves. In cellular assays, the compound's ability to inhibit autophagy is confirmed by monitoring the accumulation of the autophagy marker LC3-II or the degradation of the autophagy substrate p62 via Western blotting.
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| Cell Assay |
For cell-based assays, relevant cell lines, such as mouse embryonic fibroblasts or various cancer cell lines, are cultured in standard media. Cells are seeded and treated with MRT68921 at various concentrations for a specific duration. Following treatment, cells are harvested, and the level of autophagy is assessed by measuring LC3-II accumulation or p62 degradation via immunoblotting. Cell viability and proliferation are measured using assays like MTT or CellTiter-Glo. The impact on autophagic flux can also be evaluated using cells stably expressing a fluorescent autophagy reporter like GFP-LC3. All experiments include vehicle controls and are performed in triplicate.
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| Animal Protocol |
In vivo animal studies with MRT68921 are typically conducted in rodent models of cancer or other diseases where autophagy plays a role. The compound is formulated in a suitable vehicle, such as a mixture of DMSO, PEG, and saline, and administered via routes like intraperitoneal (IP) or oral gavage. Dosing regimens are established based on preliminary pharmacokinetic and tolerability studies. Endpoints for efficacy studies include measuring tumor growth inhibition, analyzing markers of autophagy and apoptosis in tissues, and assessing overall survival. All procedures must be conducted in accordance with institutional animal care guidelines.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic properties of MRT68921 are not extensively documented in public sources. The free base form (MW 434.58) is soluble in DMSO. For in vivo studies, it is typically formulated in vehicles that enhance its solubility and bioavailability. The compound is generally stored as a powder at -20°C to maintain stability. A comprehensive ADME profile would be necessary for a full understanding of its behavior in vivo and is crucial for interpreting results from animal efficacy studies.
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| Toxicity/Toxicokinetics |
Toxicological data for MRT68921 are limited. As a potent inhibitor of autophagy, a fundamental cellular process, its safety profile is a key consideration. The compound is intended for research use only and is not for human consumption. Potential toxicity is likely related to its on-target effects on autophagy. Comprehensive toxicology studies would be required to assess its safety for any potential therapeutic application.
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| References | |
| Additional Infomation |
MRT68921 is a research-grade chemical probe, and its primary application is in the study of autophagy and its role in various diseases, particularly cancer. It is a critical tool for dissecting the molecular mechanisms of autophagy and for target validation. The compound is not an approved drug and has not entered clinical trials. It is commercially available from various chemical suppliers for research purposes only. Its discovery has provided researchers with a powerful tool to investigate the complex role of autophagy in health and disease.
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| Molecular Formula |
C27H36N4O
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|---|---|
| Molecular Weight |
432.6009
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| Exact Mass |
434.279
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| CAS # |
1190379-70-4
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| Related CAS # |
MRT68921 dihydrochloride;2080306-21-2;MRT68921 hydrochloride;2070014-87-6
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| PubChem CID |
59225335
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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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| Index of Refraction |
1.659
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
32
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| Complexity |
624
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1CCC2=C(C1)C=CC(=C2)NC3=NC=C(C(=N3)NCCCNC(=O)C4CCC4)C5CC5
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| InChi Key |
JGKCPXMSBDYENM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H36N4O/c1-31-15-12-21-16-23(9-8-22(21)18-31)30-24-10-11-25(19-6-7-19)26(17-24)28-13-3-14-29-27(32)20-4-2-5-20/h8-11,16-17,19-20,28,30H,2-7,12-15,18H2,1H3,(H,29,32)
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| Chemical Name |
Cyclobutanecarboxylic acid {3-[2-cyclopropyl-5-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ylamino)-phenylamino]-propyl}-amide
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| Synonyms |
MRT68921 MRT-68921 MRT 68921
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3116 mL | 11.5580 mL | 23.1160 mL | |
| 5 mM | 0.4623 mL | 2.3116 mL | 4.6232 mL | |
| 10 mM | 0.2312 mL | 1.1558 mL | 2.3116 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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