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MLi-2

Cat. No. M10595
MLi-2 Structure
Synonym:

MLi2

Size Price Availability Quantity
5mg USD 187  USD187 In stock
25mg USD 687  USD687 In stock
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Quality Control
  • Current batch:
  • Purity >99%
  • COA
  • MSDS
Biological Activity

MLi-2 is a highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels.

Acute oral and subchronic dosing in MLi-2 mice resulted in dosedependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 is well tolerated over a 15-week period at brain and plasma exposures >100× the in vivo plasma IC50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, are observed in MLi-2-treated MitoPark mice.

Protocol
Cell Experiment
Cell lines SH-SY5Y cells
Preparation method A human neuroblastoma cell line, SH-SY5Y, is used for the LRRK2 stable cell line construction. SH-SY5Y cells are cultured in Dulbecco’s modified Eagle’s medium/F-12 supplemented with GlutaMax, 10% tetracycline (Tet)-free fetal bovine serum, nonessential amino acids, pen-strep at 37°C and 5% carbon dioxide. Parental cells are transfected with plasmid constructs that overexpress full-length human LRRK2 wildtype or mutant (G2019S) under the control of a Tet-inducible promoter. Transfected cells are selected and maintained with hygromycin (2 mg/ml) and zeocin (100 mg/ml). Cells are seeded into six-well plates and induced with Tet (2 mg/ml) for 72 hours prior to treatment. After 90 minutes of MLi-2 incubation, cells were mechanically lifted, pelleted, and lysed with lysis buffer supplemented with protease, and phosphatase inhibitors. Pellets are further bead homogenized and then spun at 13,200 rpm for 20 minutes at 4°C. Supernatants are then removed for subsequent Western blot analyses.
Concentrations 10 serial 3-fold dilutions, top concentration 5 μM
Incubation time 90 min
Animal Experiment
Animal models male C57Bl/6 mice weighing 20-25g
Formulation suspended in 30% Captisol
Dosages 1-100 mg/kg; administered in a volume of 10 ml/kg
Administration IV or PO administration
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information
Molecular Weight 379.46
Formula C21H25N5O2
CAS Number 1627091-47-7
Purity >99%
Solubility DMSO 60 mg/mL
Storage at -20°C
References

[1] Jack D Scott, et al. J Med Chem. Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity

[2] Matthew J Fell, et al. J Pharmacol Exp Ther. MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

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  Catalog
Abmole Inhibitor Catalog




Keywords: MLi-2, MLi2 supplier, LRRK2, inhibitors

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