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| Targets |
MLKL[1]
The primary target of MLKL-IN-2 is MLKL (mixed lineage kinase domain-like protein), the terminal executioner of the necroptosis pathway. MLKL is a pseudokinase that, upon phosphorylation by RIPK3, oligomerizes and translocates to the plasma membrane, where it disrupts membrane integrity and induces necroptotic cell death. By inhibiting MLKL, MLKL-IN-2 blocks this terminal step of necroptosis. This inhibition prevents the uncontrolled release of damage-associated molecular patterns (DAMPs) and inflammatory mediators that contribute to tissue damage in various diseases. MLKL-IN-2 thus holds therapeutic potential for treating diseases where necroptosis contributes to pathology. |
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| ln Vitro |
As a specific inhibitor of MLKL, MLKL-IN-2 exerts biological effects by targeting MLKL, a key effector protein in the necroptosis pathway. Although its exact IC₅₀ value has not been publicly reported, similar MLKL inhibitors have been shown to alter intracellular trafficking, inhibit the constitutive release of extracellular vesicles (EVs), reduce the expansion of glioblastoma stem-like cells (GSCs), and increase GSC death in vitro, while also potentiating the efficacy of temozolomide, a chemotherapeutic agent. Given its mechanism of action as an MLKL inhibitor, it is inferred to interfere with MLKL-mediated necroptosis and related cellular processes, though direct experimental data on its specific in vitro activity (such as anti-necroptotic potency in various cell lines) remains limited to patent information without detailed public reports.
Specific in vitro activity data for MLKL-IN-2 is not detailed in the provided literature. As an MLKL inhibitor, it would be expected to block MLKL-mediated necroptosis in cellular models. Its activity would be characterized by its ability to inhibit MLKL oligomerization, membrane translocation, and subsequent cell death in response to necroptotic stimuli (e.g., TNF-α + SMAC mimetic + zVAD). The compound's potency would be determined by measuring its IC50 for inhibition of MLKL-mediated cell death. MLKL-IN-2 is supplied as a solid with a purity of 98% and is soluble in DMSO at 10 mg/mL. |
| ln Vivo |
Publicly available data on the in vivo activity of MLKL-IN-2 is scarce, with no direct reports on its pharmacodynamic effects in animal models. However, pharmacological inhibition of MLKL has been demonstrated to reduce tumor burden and the level of plasmatic extracellular vesicles in in vivo studies of glioblastoma, suggesting a potential therapeutic role for MLKL inhibitors in tumor treatment. As a specific MLKL-targeting agent, MLKL-IN-2 may exhibit similar in vivo effects, such as suppressing MLKL-related pathological processes (e.g., tumor growth, inflammatory responses) through inhibiting MLKL activity, but further in vivo experiments are required to confirm its efficacy, optimal dosage, and therapeutic window.
In vivo, MLKL-IN-2 would be expected to exert therapeutic effects in disease models where necroptosis contributes to pathology, including neurodegeneration, ischemia-reperfusion injury, and inflammatory disorders. By inhibiting MLKL, the compound would block the execution of necroptosis, reducing tissue damage and inflammation. Its in vivo efficacy would be assessed in animal models of these diseases, with endpoints including tissue damage, inflammatory markers, and functional outcomes. MLKL-IN-2 is for research use only and is not intended for human therapeutic use. |
| Enzyme Assay |
In vitro binding and enzyme activity assays for MLKL-IN-2 would typically involve measuring its ability to inhibit MLKL function. These assays could include binding studies to determine the compound's affinity for MLKL, as well as functional assays to measure its ability to block MLKL oligomerization and membrane translocation. The compound's selectivity for MLKL over other kinases and pseudokinases would be confirmed by testing against a panel of related targets.
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| Cell Assay |
Cellular assays for MLKL-IN-2 involve treating cells with the compound and then inducing necroptosis using stimuli such as TNF-α + SMAC mimetic + zVAD. The compound's ability to inhibit MLKL-mediated cell death is assessed by measuring cell viability, lactate dehydrogenase (LDH) release, or other markers of necroptosis. MLKL-IN-2's ability to block MLKL oligomerization and membrane translocation can also be assessed by immunofluorescence or biochemical fractionation.
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| Animal Protocol |
In vivo efficacy of MLKL-IN-2 would be evaluated in animal models of diseases where necroptosis plays a pathogenic role. The compound could be administered via intraperitoneal or oral routes, depending on its pharmacokinetic properties. Efficacy endpoints would include reduction of tissue damage, inflammatory markers, and improvement in functional outcomes. For example, in models of ischemia-reperfusion injury, MLKL-IN-2 would be expected to reduce infarct size and improve organ function. In models of neurodegeneration, it would be expected to reduce neuronal loss and improve behavioral outcomes.
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| ADME/Pharmacokinetics |
MLKL-IN-2 has a molecular weight of 423.51 and a molecular formula of C26H25N5O. It is supplied as a solid with a purity of 98%. The compound is soluble in DMSO at 10 mg/mL. It should be stored as a powder at -20°C for up to 3 years or at 4°C for up to 2 years. The compound is for research use only and is not intended for human therapeutic use.
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| Toxicity/Toxicokinetics |
No specific toxicity data is available for MLKL-IN-2 in the provided literature. As a research compound, its safety profile would be an important consideration for in vivo applications. Potential toxicities could be related to its effects on MLKL-mediated necroptosis in various tissues. Standard preclinical safety studies would be required to evaluate its safety for potential therapeutic applications. The compound is for research use only and is not intended for human therapeutic use.
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| References | |
| Additional Infomation |
MLKL-IN-2 is a small-molecule inhibitor of MLKL, the terminal executioner of the necroptosis pathway. It is compound (i) from patent WO2021224505A1. MLKL-IN-2 has a molecular formula of C26H25N5O and a molecular weight of 423.51. By inhibiting MLKL, the compound blocks the execution of necroptosis while preserving other cell death pathways such as apoptosis. MLKL-IN-2 holds therapeutic potential for treating diseases where necroptosis contributes to pathology, including neurodegeneration, ischemia-reperfusion injury, and inflammatory disorders. It is a research tool and is not approved for clinical use.
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| Molecular Formula |
C26H25N5O
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| Molecular Weight |
423.509605169296
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| Exact Mass |
423.205
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| CAS # |
899759-16-1
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| PubChem CID |
7593182
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| Appearance |
White to light yellow solid powder
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| LogP |
3.9
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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 |
32
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| Complexity |
621
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CC=C2C=CC=CC2=C1)NC1=CC=CC(=C1)C1=CC=C(N=N1)N1CCN(C)CC1
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| InChi Key |
CVHOXUUPSXOTPM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H25N5O/c1-30-13-15-31(16-14-30)25-12-11-24(28-29-25)21-7-4-8-23(18-21)27-26(32)22-10-9-19-5-2-3-6-20(19)17-22/h2-12,17-18H,13-16H2,1H3,(H,27,32)
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| Chemical Name |
N-[3-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]phenyl]naphthalene-2-carboxamide
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| Synonyms |
MLKL-IN-2; MLKL-IN 2; MLKL-IN2; 899759-16-1; TCMDC-125349; N-(3-(6-(4-methylpiperazin-1-yl)pyridazin-3-yl)phenyl)-2-naphthamide; N-{3-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]phenyl}naphthalene-2-carboxamide;
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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: 10 mg/mL (23.61 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (2.36 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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 mg/mL (2.36 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 10.0 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: ≥ 1 mg/mL (2.36 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 | 2.3612 mL | 11.8061 mL | 23.6122 mL | |
| 5 mM | 0.4722 mL | 2.3612 mL | 4.7224 mL | |
| 10 mM | 0.2361 mL | 1.1806 mL | 2.3612 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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