Home Autophagy LRRK2 inhibitor MLi-2 For research use only.

MLi-2

MLi-2 is an orally active and highly selective inhibitor of LRRK2. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro with IC50 of 0.76 nM, a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 with IC50 of 1.4 nM, and a radioligand competition binding assay with IC50 of 3.4 nM.

MLi-2 Chemical Structure

MLi-2 Chemical Structure

CAS No. 1627091-47-7

Purity & Quality Control

MLi-2 Related Products

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
SH-SY5Y Function assay 90 mins Inhibition LRRK2 G2019S mutant Ser935 phosphorylation in human SH-SY5Y cells after 90 mins by Western blot analysis, IC50 = 0.0048 μM. 28245354
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Biological Activity

Description MLi-2 is an orally active and highly selective inhibitor of LRRK2. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro with IC50 of 0.76 nM, a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 with IC50 of 1.4 nM, and a radioligand competition binding assay with IC50 of 3.4 nM.
Targets
LRRK2 [1]
(purified LRRK2 kinase assay in vitro)		 LRRK2 [1]
(cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2)		 LRRK2 [1]
(radioligand competition binding assay)
0.76 nM 1.4 nM 3.4 nM
In vitro
In vitro

MLi-2 is a structurally novel, 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.[1]
Cell Research Cell lines SH-SY5Y cells
Concentrations 10 serial 3-fold dilutions, top concentration 5 μM
Incubation Time 90 min
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.
In Vivo
In vivo

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.[1]
Animal Research Animal Models male C57Bl/6 mice
Dosages 1 mg/kg, 2 mg/kg, 3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg
Administration IV, Oral gavage

Chemical Information & Solubility

Molecular Weight 379.46 Formula

C21H25N5O2
CAS No. 1627091-47-7 SDF --
Smiles CC1CN(CC(C)O1)C2=CC(=NC=N2)C3=N[NH]C4=CC=C(OC5(C)CC5)C=C34
Storage (From the date of receipt) 3 years -20°C powder

In vitro
Batch:

DMSO : 76 mg/mL ( (200.28 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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