MLi-2

Protein target name:

LRRK2

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

Tocris

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

TKL

HUGO ID:

HGNC:18618

Entrez gene ID:

120892

UNIPROT ID:

Q5S007

Target alias:

AURA17, DARDARIN, PARK8, RIPK7, ROCO2

Probe Details

Chemical Probes Portal ID:

CPP1881

PubChem CID:

78319901

ChEMBL ID:

CHEMBL4098877

SMILES string:

C1C=C(C(=CC=1OC1(C)CC1)C1C2=NC=NC(=C2)N2C[C@@](O[C@@](C2)(C)[H])(C)[H])NN=1

InChi Key:

ATUUNJCZCOMUKD-OKILXGFUSA-N

Control compound:

MLi-2-NC

Orthogonal probe:

GNE7915

Physico-chemical properties

Solubility - preferred solvent:

10 - 20 mM in DMSO

NMR:

1H NMR (500 MHz, CDCl3) δ 10.33 (s, 1H), 8.79 (d, J = 1.0 Hz, 1H), 8.31 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.34 (s, 1H), 7.15 (dd, J = 9.0, 2.5 Hz, 1H), 4.35–4.29 (m, 2H), 3.72 (m, 2H), 2.68 (dd, J = 13.0, 10.5 Hz, 2H), 1.66 (s, 3H), 1.30 (d, J = 6.0 Hz, 6H), 1.13–1.07 (m, 2H), 0.84–0.77 (m, 2H).

13C NMR (126 MHz, CDCl3) δ 161.94, 159.27, 158.45, 152.76, 143.01, 137.65, 122.39, 120.13, 110.68, 106.65, 98.08, 71.53, 56.60, 49.26, 20.16, 18.85, 13.68.

Storage Recommendations

Storage (solution):

-20°C

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

1.8 nM

Potency assay:

MSD and Invitrogen assay

PDB ID for probe-target interaction (3D structure):

5U6I

Structure-activity relationship:

yes see ref. DOI: 10.1021/acs.jmedchem.7b00045

Off target activity

Potency (off target):

IC50

Potency assay (off target):

KinomeScan

Probe Selectivity in Vitro:

> 100-fold kinome selective with IC50 < 1 µM for the following kinases: CLK4 (225 nM), MAP3K14 (244 nM), MAP3K5 (428 nM), CLK2 (605 nM), and TTK (935 nM).

In cell validation

On target activity in cells

Potency in cells:

IC50

3.5 nM

Potency assay (cells):

LRRK2 G2019S SH-SY5Y human neuroblastoma cell line was used for the LRRK2 pSer935 phosphorylation measurements.

Off target activity in cells

Potency assay, off target (cells):

PanLabs Profiling

Probe Selectivity in Cell:

PanLabs Profile shows 5 hits > 50% inhibition (@ 10 μM): HTR2B (1.2 µM), SLC6A2 (3.8 µM), CHRM2 (6.4 µM), PPARG (6.5 µM), adenosine transporter (9.7 µM). NanoBRET results (SGC Frankfurt): CLK4 IC50 = 971 nM, MAP3K14 IC50 = 29.7 µM, MAP3K5 IC50 > 20 µM, CLK2 IC50 = 1,.38 µM, TTK IC50 = 6.62 µM

In vivo validation

Organism:

MouseRat

Dose:

30 mg/Kg Oral2 mg/Kg IV

Route of delivery:

OralIntravenous

Fraction of probe bound to plasma protein:

39%

Cmax:

0.38 uM

Tmax:

1.3 h

Organ of Interest

Organ (O):

Brain

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.7b00045

Reference (PMID):

28245354

External Resources

Available data:

SGC additional analysis

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

Part of the Donated Chemical Probes initiative from SGC.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

In a mouse model of idiopathic PD, MLi-2 was well-tolerated and showed robust target engagement. However, LRRK2 kinase inhibition in the MitoPark model did not prevent motor dysfunction, α-synuclein pathology or neuron death.

Jun 9 2020 - 5:22pm

While there are multiple commercially available LRRK inhibitors available, MLi-2 provides another quality chemical probe to help validate this target in cell-based assays.

Jul 3 2020 - 2:48pm

MLi-2

Probe Availability

Probe Information

Target Details

AURA17, DARDARIN, PARK8, RIPK7, ROCO2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?

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MLi-2

Probe Availability

Probe Information

Target Details

AURA17, DARDARIN, PARK8, RIPK7, ROCO2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?