LRRK2-IN-1   Click here for help

GtoPdb Ligand ID: 9396

Synonyms: LRRK2-IN1 | LRRK2IN1 [2]
PDB Ligand
Compound class: Synthetic organic
Comment: LRRK2-IN-1 is a selective inhibitor of the Parkinson's associated kinase LRRK2 (leucine rich repeat kinase 2) [1]. The compound has limited brain penetrance. LRRK2-IN-1 is used as a pharmacological tool to interrogate the function of LRRK2 in Parkinson's disease.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 100.76
Molecular weight 570.31
XLogP 4.66
No. Lipinski's rules broken 0
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Canonical SMILES COc1cc(ccc1Nc1ncc2c(n1)n(C)c1ccccc1c(=O)n2C)C(=O)N1CCC(CC1)N1CCN(CC1)C
Isomeric SMILES COc1cc(ccc1Nc1ncc2c(n1)n(C)c1ccccc1c(=O)n2C)C(=O)N1CCC(CC1)N1CCN(CC1)C
InChI InChI=1S/C31H38N8O3/c1-35-15-17-38(18-16-35)22-11-13-39(14-12-22)29(40)21-9-10-24(27(19-21)42-4)33-31-32-20-26-28(34-31)36(2)25-8-6-5-7-23(25)30(41)37(26)3/h5-10,19-20,22H,11-18H2,1-4H3,(H,32,33,34)
Bioactivity Comments
LRRK2-IN-1 inhibits activity of the LRRK2 G2019S activating mutation with an IC50 of 6nM [1]. In patient derived lymphoblastoid cells and in mouse in vivo studies, treatment with LRRK2-IN-1 suppresses LRRK2 kinase activity resulting in dephosphorylation of Ser910 and Ser935 and loss of 14-3-3 binding with resultant re-distribution and accumulation of LRRK2 in aggregate fibrillar structures in the cytoplasm.
Kinase profile screening in biochemical assays identifies DCLK2, DCLK1 and MAPK7 as potential off-targets. LRRK1 inhibition could not be evaluated under the same assay conditions as LRRK2 inhibition [1].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
leucine rich repeat kinase 2 Primary target of this compound Hs Inhibitor Inhibition 8.2 pKi - 2
pKi 8.2 (Ki 6x10-9 M) [2]
Description: Biochemical assay dissociation constant.
leucine rich repeat kinase 2 Primary target of this compound Hs Inhibitor Inhibition 7.9 pIC50 - 1
pIC50 7.9 (IC50 1.3x10-8 M) [1]
Description: With 0.1 mM ATP in the assay.