MLi-2

Inhibitor of LRRK2

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe MLi-2 is in the process of SERP review.

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Information

LRRK2

Inhibitor

Additional Data

SGC image SGC Chemical Probe Collection

Probe Availability:

In Vitro Validations

Uniprot ID: Q5S007

Target Class: Protein kinase

Target SubClass: TKL

Potency: IC50

Potency Value: 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

Target aliases:

Leucine-rich repeat serine/threonine-protein kinas ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : 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).

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

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP 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.

(last updated: 5 Jun 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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.

(last updated: 3 Jul 2020 )