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HG-10-102-01

HG-10-102-01 : Inhibitor of LRRK2

Structure

Information

  • LRRK2 (Mutant:WT, G2019S, A2016T, G2019S-A2016T)
  • Inhibitor
  • up to 1 µM

In Vitro Validations

Uniprot ID: Q5S007
Target Class: Kinase
Target SubClass: TKL
Potency: IC50
Potency Value: 20.3 nM
Potency Assay: Biochemical inhibition of WT GST-LRRK2 in the presence of 100 μM ATP.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Leucine-rich repeat serine/threonine-protein kinas ...

DOI Reference: 10.1021/ml300123a

Uniprot ID: Q5S007
Target Class: Kinase
Target SubClass: TKL
Potency: IC50
Potency Value: 3.2 nM
Potency Assay: Biochemical inhibition of G2019S GST-LRRK2 in the presence of 100 μM ATP.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Leucine-rich repeat serine/threonine-protein kinas ...

DOI Reference: 10.1021/ml300123a

Uniprot ID: Q5S007
Target Class: Kinase
Target SubClass: TKL
Potency: IC50
Potency Value: 153.7 nM
Potency Assay: Biochemical inhibition of A2016T GST-LRRK2 in the presence of 100 μM ATP.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Leucine-rich repeat serine/threonine-protein kinas ...

DOI Reference: 10.1021/ml300123a

Uniprot ID: Q5S007
Target Class: Kinase
Target SubClass: TKL
Potency: IC50
Potency Value: 95.9 nM
Potency Assay: Biochemical inhibition of G2019S-A2016T GST-LRRK2 in the presence of 100 μM ATP.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Leucine-rich repeat serine/threonine-protein kinas ...

DOI Reference: 10.1021/ml300123a

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): The kinase selectivity of was assessed using standard radioactivity-based enzymatic assays against a panel of 138 kinases (Dundee profiling). At a concentration of 10 μM, only inhibited the kinase activities of mixed-lineage kinase 1 (MLK1) and MAP kinase-interacting serine/threonine-protein kinase 2 (MNK2) to greater than 80% of the dimethyl sulfoxide (DMSO) control. Dose–response analysis revealed inhibition of MLK1 with an IC50 = 2.1 μM and MNK2 with an IC50 = 0.6 μM. KinomeScan analysis against a near comprehensive panel of 451 kinases at a concentration of 1 μM resulted in no interactions detected with kinases other than LRRK2[G2019S] with the exception of one mutant form of c-Kit (L576P).
Potency assay, off target (cells): KiNativ approach to monitoring kinase inhibition in tissues from the inhibitor-treated animals. Of the kinases profiled, only LRRK2 showed a clear and significant dose-related increase in engagement with HG-10-102-01.
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

HG-10-102-01 is an excellent chemical probe to investigate LRRK2 signalling in cells, highly recommended. Its selectivity profile is outstanding, and if this probe is used up to the recommended 1 uM concentration in cells; one can confidently link the observed phenotype to LRRK2 inhibition. Importantly however, target engagement - e.g. via monitoring LRRK2 phosphorylation at Ser910 and Ser935 in a hypothesis-relevant cellular model, must be provided; also recommend to include orthogonal LRRK2 inhibitors. Note that HG-10-102-01 also inhibits LRRK2[A2016T+G2019S] and LRRK2[A2016T], thus these mutants cannot be used to validate whether the phenotype observed with HG-10-102-01 is indeed LRRK2-dependent. Inclusion of orthogonal LRRK2 inhibitors is critical for robustness of data. HG-10-102-01 can be also used in vivo, as it shows good BBB permeability and there is evidence of LRRK2 inhibition in the brain, however, it has a short in vivo half-life which might cause insufficient (or extremely short) LRRK2 inhibition in vivo. Results obtained with HG-10-102-01 from animal models should be backed up with data obtained via targeting LRRK2 with molecular probes.

(last updated: 1 Feb 2023 )