| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| Other Sizes |
| Targets |
IC50: 0.76 nM (LRRK2)[1]
MLi-2 targets leucine-rich repeat kinase 2 (LRRK2), a kinase implicated in both familial and sporadic Parkinson's disease. Mutations in LRRK2 are among the most common genetic causes of Parkinson's disease, making it a key therapeutic target. |
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| ln Vitro |
MLi-2 demonstrates remarkable efficacy in three different assays: radioligand competition Binding (IC50=3.4 nM), cellular test monitoring LRRK2 pSer935 LRRK2 dephosphorylation (IC50=1.4 nM), and purified LRRK2 kinase assay in vitro (IC50=0.76 nM). Over 300 kinases, as well as a range of receptors and ion channels, are more than 295-fold selective for MLi-2 [1].
In vitro, MLi-2 potently inhibits LRRK2 kinase activity with an IC50 of 0.76 nM in a purified enzyme assay. In cell-based assays monitoring LRRK2 pSer935 dephosphorylation, it shows an IC50 of 1.4 nM. In radioligand competition binding assays, it exhibits an IC50 of 3.4 nM. |
| ln Vivo |
Dephosphorylation of pSer935 LRRK2 was used to measure the dose-dependent suppression of central and peripheral targets in MLi-2 mice treated acutely or subchronically over a 24-hour period. Over a period of 15 weeks, MLi-2 treatment in MitoPark mice resulted in well-tolerated brain and plasma exposure. MitoPark mice treated with MLi-2 showed alterations in lung morphology that were in line with increased type II pneumocytes [1].
In vivo, MLi-2 is orally active and brain-penetrant, making it suitable for central nervous system applications. It has shown potential in preclinical models of Parkinson's disease by inhibiting LRRK2 kinase activity in the brain. The compound's high potency and selectivity support its use in investigating LRRK2 biology. |
| Enzyme Assay |
The in vitro enzyme inhibition assay for MLi-2 involves measuring the kinase activity of purified LRRK2 in the presence of the compound. The assay uses a peptide substrate and ATP, and the phosphorylation is quantified using a radiometric or fluorescence-based method. The IC50 is determined by plotting the percentage of remaining activity against compound concentration.
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| Cell Assay |
Cellular assays for MLi-2 involve measuring LRRK2 phosphorylation at Ser935 in cells treated with the compound. Cells are incubated with MLi-2 at various concentrations, and the level of LRRK2 pSer935 is detected by Western blot using a phospho-specific antibody. The EC50 for inhibition of LRRK2 autophosphorylation is determined.
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| Animal Protocol |
In vivo efficacy of MLi-2 is evaluated in mouse and rat models of Parkinson's disease. The compound is typically administered orally, and LRRK2 kinase activity in brain tissue is measured by assessing the phosphorylation of LRRK2 substrates. Behavioral assays may also be performed to evaluate functional outcomes.
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| ADME/Pharmacokinetics |
MLi-2 is orally bioavailable and brain-penetrant, with favorable pharmacokinetic properties. It has a molecular weight of 379.46 g/mol and a molecular formula of C21H25N5O2. Further ADME parameters such as half-life and clearance have been characterized in preclinical studies.
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| Toxicity/Toxicokinetics |
Toxicity data for MLi-2 are limited. As a potent LRRK2 inhibitor, it has been evaluated in preclinical safety studies. No significant toxicity has been reported at efficacious doses.
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| References | |
| Additional Infomation |
MLI-2 is an indazole compound with the structure 1H-indazole, substituted at position 3 with a 6-(cis-2,6-dimethylmorpholin-4-yl)pyrimidin-4-yl group and at position 5 with a (1-methylcyclopropoxy) group. It is an inhibitor of leucine-rich repeat kinase 2 (LRRK2), belonging to EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitors. It belongs to the indazole, pyrimidine, morpholino, cyclopropane, aromatic ether, and tertiary amine classes of compounds.
MLi-2 is a research compound and has not yet received regulatory approval. It is a highly potent and selective LRRK2 inhibitor with central nervous system activity, making it a valuable tool for studying LRRK2 biology and Parkinson's disease. |
| Molecular Formula |
C21H25N5O2
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|---|---|
| Molecular Weight |
379.4555
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| Exact Mass |
379.2
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| Elemental Analysis |
C, 66.47; H, 6.64; N, 18.46; O, 8.43
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| CAS # |
1627091-47-7
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| PubChem CID |
78319901
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
625.8±55.0 °C at 760 mmHg
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| Flash Point |
332.3±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.628
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| LogP |
3.42
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
549
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O(C1C([H])=C([H])C2=C(C(C3=C([H])C(=NC([H])=N3)N3C([H])([H])[C@@]([H])(C([H])([H])[H])O[C@@]([H])(C([H])([H])[H])C3([H])[H])=NN2[H])C=1[H])C1(C([H])([H])[H])C([H])([H])C1([H])[H]
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| InChi Key |
ATUUNJCZCOMUKD-OKILXGFUSA-N
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| InChi Code |
InChI=1S/C21H25N5O2/c1-13-10-26(11-14(2)27-13)19-9-18(22-12-23-19)20-16-8-15(28-21(3)6-7-21)4-5-17(16)24-25-20/h4-5,8-9,12-14H,6-7,10-11H2,1-3H3,(H,24,25)/t13-,14+
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| Chemical Name |
(2S,6R)-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine
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| Synonyms |
MLi-2 MLi 2 MLi2.
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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 : ~50 mg/mL (~131.77 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.87 mg/mL (7.56 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.87 mg/mL (7.56 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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 (6.59 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. Solubility in Formulation 4: ≥ 2.5 mg/mL (6.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. Solubility in Formulation 5: 5 mg/mL (13.18 mM) in 30 % SBE-β-CD (add these co-solvents sequentially from left to right, and one by one), Suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6353 mL | 13.1766 mL | 26.3532 mL | |
| 5 mM | 0.5271 mL | 2.6353 mL | 5.2706 mL | |
| 10 mM | 0.2635 mL | 1.3177 mL | 2.6353 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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