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MLi-2 | Inhibitor of LRRK2
RATINGS:
Cellular Use: (2 reviews)

In Model Organisms: (2 reviews)
Probe Summary
Selectivity
Potency
In Vivo
Control Compounds
Chemical Information
References
Vendors
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Probe Summary

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Targets Biochemical/Biophysical Potency Cellular Potency
LRRK2
  • IC50:1.8 nM
  • IC50:3.5 nM
Inhibitor
up to 1 uM

Selectivity

In Vitro Selectivity Assessment

Potency: IC50

Potency Assay Off-Target:
KinomeScan
Selectivity Assessment Description:
> 100-fold kinome selective with IC50 < 1 µM for the following kinases: CLK4 (225 nM), MAP3 ...
In Cell Selectivity Assessment
Potency Assay Off-Target:
PanLabs Profiling
Selectivity Assessment Description:
PanLabs Profile shows 5 hits > 50% inhibition (@ 10 μM): HTR2B (1.2 µM), SLC6A2 (3.8 µM), CHRM ...

Potency
Cellular
In Vitro

LRRK2

Mode of Action: Inhibitor

Structure-Activity-Relationship data available? Yes

DOI Reference: 10.1021/acs.jmedchem.7b00045

In Vivo Validations

Rat
Dose: 2 mg/Kg
Route of delivery: Intravenous
Plasma half life: 1.8 ± 1.0 h
Systemic clearance: 153 ± 55 mL/min/Kg
Cmax: 1.17 ± 0.15 μM
Area Under the Curve:: 0.66 ± 0.24 μM·h
Organ of interest (O): Brain

DOI Reference: 10.1021/acs.jmedchem.7b00045

Dose: 10 mg/Kg
Route of delivery: Oral
Cmax: 0.48 ± 0.36 μM
Tmax: 1.3 ± 0.75 h
Area Under the Curve:: 1.3 ± 0.56 μM·h
Bioavailability: 39 ± 18%

DOI Reference: 10.1021/acs.jmedchem.7b00045

Negative Control Compounds

MLi-2-NC
Notes: LRRK2 potency 1000x less: MLi-2-NC (IC50 = 6480 nM) NanoBRET assay (SGC Frankfurt) (EC50 [µM]; n = 3): LRRK2 (> 50), CLK4 (6.2 ± 1.2), MAP3K14 (> 50), MAP3K5 (4.1 ± 1.7), CLK2 (11 ± 1.7), TTK (> 50) Clean GPCR scan except for activity on TMEM97 (Ki = 1074.98 nM) and SIGMAR1 (Ki = 1593.68 nM)

Orthogonal Probes def

GNE7915

Chemical Information

Molecular Formula C21H25N5O2
SMILEs C[C@H]1CN(c2cc(-c3n[nH]c4ccc(OC5(C)CC5)cc34)ncn2)C[C@@H](C)O1
InChI 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+
Molecular weight 379.20 Da
AlogP 3.5648000000000026
HBond acceptors 7
HBond donors 1
Atoms 53

Vendors

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Expert Reviews

by SERP
(on 5 Jun 2020)
Cellular Use Rating
In Model Organisms
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...
by SERP
(on 3 Jul 2020)
Cellular Use Rating
In Model Organisms
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.
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