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leucine rich repeat kinase 2

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Target not currently curated in GtoImmuPdb

Target id: 2059

Nomenclature: leucine rich repeat kinase 2

Abbreviated Name: LRRK2

Family: Leucine-rich repeat kinase (LRRK) family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 2527 12q12 LRRK2 leucine rich repeat kinase 2
Mouse - 2527 15 E3 Lrrk2 leucine-rich repeat kinase 2
Rat - 2526 7q35 Lrrk2 leucine-rich repeat kinase 2
Previous and Unofficial Names Click here for help
Park8 | Parkinson disease (autosomal dominant) 8 | ROCO2 | RIPK7 | leucine-rich repeat kinase 2
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase
PDB Id:  3D6T
Resolution:  2.43Å
Species:  Human
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06454589).
PDB Id:  4W8D
Ligand:  PF-06454589
Resolution:  1.77Å
Species:  Human
References:  11
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GNE-0877 Small molecule or natural product Primary target of this compound Hs Inhibition 9.1 pKi 8
pKi 9.1 (Ki 7x10-10 M) [8]
Description: In a biochemical assay
GNE-7915 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Binding 9.0 pKi 8
pKi 9.0 (Ki 1x10-9 M) [8]
HG-10-102-01 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.5 pKi 4
pKi 8.5 (Ki 3x10-9 M) [4]
LRRK2-IN-1 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.2 pKi 12
pKi 8.2 (Ki 6x10-9 M) [12]
Description: Biochemical assay dissociation constant.
NIK SMI1 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.6 pKi 3
pKi 6.6 (Ki 2.478x10-7 M) [3]
TTT-3002 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pIC50 15
pIC50 9.1 (IC50 7x10-10 M) [15]
Description: Measuring inhibition of LRRK2-catalyzed phosphorylation of the specific peptide substrate LRRKtide iv vitro
compound 20 [PMID: 30998356] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 13
pIC50 9.0 (IC50 1x10-9 M) [13]
Description: Measuring in vitro enzyme inhibitory activity.
PF-06447475 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.5 pIC50 11
pIC50 8.5 (IC50 3x10-9 M) [11]
Description: Biochemical assay using Invitrogen's Lantha Screen technology.
GNE-7915 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 8
pIC50 8.1 (IC50 9x10-9 M) [8]
Description: Inhibition of autophosphorylation in a cellular assay.
URMC-099 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pIC50 10
pIC50 8.0 (IC50 1.1x10-8 M) [10]
PF-06454589 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.9 pIC50 11
pIC50 7.9 (IC50 1.2x10-8 M) [11]
LRRK2-IN-1 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.9 pIC50 7
pIC50 7.9 (IC50 1.3x10-8 M) [7]
Description: With 0.1 mM ATP in the assay.
GNE-9605 Small molecule or natural product Primary target of this compound Hs Inhibition 7.7 pIC50 8
pIC50 7.7 (IC50 1.9x10-8 M) [8]
JAK3 inhibitor VI Small molecule or natural product Hs Inhibition 7.7 pIC50
pIC50 7.7 (IC50 2.2x10-8 M)
NIK inhibitor 12f Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 pIC50 16
pIC50 7.0 (IC50 9.46x10-8 M) [16]
Description: Inhibitory concentration determined in a Reaction Biology kinase sreening assay.
GSK2646264 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 5.4 pIC50 2
pIC50 5.4 (IC50 3.981x10-6 M) [2]
DCLK1-IN-1 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.2 pIC50 9
pIC50 5.2 (IC50 6.97x10-6 M) [9]
Description: Determined in a LRRK2 ADAPTA kinase assay.
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 5,14

Key to terms and symbols Click column headers to sort
Target used in screen: LRRK2
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.9 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.1 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
ruxolitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.5 pKd
Target used in screen: LRRK2(G2019S)
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.4 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.1 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 8.6 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 7.3 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.2 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
ruxolitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: ...1

Key to terms and symbols Click column headers to sort
Target used in screen: nd/LRRK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 0.3
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.3
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.4
SU6656 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.8
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 1.9
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.2
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 3.3
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 6.2
SU11274 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 3 GO processes
GO:0006897 endocytosis IMP
GO:1900242 regulation of synaptic vesicle endocytosis IDA
click arrow to show/hide IEA associations
GO:1900244 positive regulation of synaptic vesicle endocytosis IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:1903980 positive regulation of microglial cell activation IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:1903980 positive regulation of microglial cell activation IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:1904469 positive regulation of tumor necrosis factor secretion IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 3 GO processes
GO:0031398 positive regulation of protein ubiquitination IDA
GO:1902499 positive regulation of protein autoubiquitination IDA
click arrow to show/hide IEA associations
GO:1903980 positive regulation of microglial cell activation IEA
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Parkinson disease 8, autosomal dominant; PARK8
Synonyms: Hereditary Parkinson disease with late-onset [Orphanet: ORPHA411602]
Parkinson's disease [Disease Ontology: DOID:14330]
Disease Ontology: DOID:14330
OMIM: 607060
Orphanet: ORPHA411602

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Barker MD, Liddle J, Atkinson FL, Wilson DM, Dickson MC, Ramirez-Molina C, Lewis H, Davis RP, Somers DO, Neu M et al.. (2018) Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. Bioorg. Med. Chem. Lett., 28 (21): 3458-3462. [PMID:30249354]

3. Brightbill HD, Suto E, Blaquiere N, Ramamoorthi N, Sujatha-Bhaskar S, Gogol EB, Castanedo GM, Jackson BT, Kwon YC, Haller S et al.. (2018) NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nat Commun, 9 (1): 179. [PMID:29330524]

4. Chen H, Chan BK, Drummond J, Estrada AA, Gunzner-Toste J, Liu X, Liu Y, Moffat J, Shore D, Sweeney ZK et al.. (2012) Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling. J. Med. Chem., 55 (11): 5536-45. [PMID:22591441]

5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

6. Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR. (2008) Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc. Natl. Acad. Sci. U.S.A., 105 (5): 1499-504. [PMID:18230735]

7. Deng X, Dzamko N, Prescott A, Davies P, Liu Q, Yang Q, Lee JD, Patricelli MP, Nomanbhoy TK, Alessi DR et al.. (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat. Chem. Biol., 7 (4): 203-5. [PMID:21378983]

8. Estrada AA, Chan BK, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, Chen H, Dominguez SL, Dotson J, Drummond J et al.. (2014) Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J. Med. Chem., 57 (3): 921-36. [PMID:24354345]

9. Ferguson FM, Nabet B, Raghavan S, Liu Y, Leggett AL, Kuljanin M, Kalekar RL, Yang A, He S, Wang J et al.. (2020) Discovery of a selective inhibitor of doublecortin like kinase 1. Nat. Chem. Biol., 16 (6): 635-643. [PMID:32251410]

10. Goodfellow VS, Loweth CJ, Ravula SB, Wiemann T, Nguyen T, Xu Y, Todd DE, Sheppard D, Pollack S, Polesskaya O et al.. (2013) Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J. Med. Chem., 56 (20): 8032-48. [PMID:24044867]

11. Henderson JL, Kormos BL, Hayward MM, Coffman KJ, Jasti J, Kurumbail RG, Wager TT, Verhoest PR, Noell GS, Chen Y et al.. (2015) Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor. J. Med. Chem., 58 (1): 419-32. [PMID:25353650]

12. Kavanagh ME, Doddareddy MR, Kassiou M. (2013) The development of CNS-active LRRK2 inhibitors using property-directed optimisation. Bioorg. Med. Chem. Lett., 23 (13): 3690-6. [PMID:23721803]

13. Riggs JR, Elsner J, Cashion D, Robinson D, Tehrani L, Nagy M, Fultz KE, Krishna Narla R, Peng X, Tran T et al.. (2019) Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy. J. Med. Chem., 62 (9): 4401-4410. [PMID:30998356]

14. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

15. Yao C, Johnson WM, Gao Y, Wang W, Zhang J, Deak M, Alessi DR, Zhu X, Mieyal JJ, Roder H et al.. (2013) Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity. Hum. Mol. Genet., 22 (2): 328-44. [PMID:23065705]

16. Zhu Y, Ma Y, Zu W, Song J, Wang H, Zhong Y, Li H, Zhang Y, Gao Q, Kong B et al.. (2020) Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis. J Med Chem, 63 (13): 6748-6773. [PMID:32479083]

How to cite this page

Leucine-rich repeat kinase (LRRK) family: leucine rich repeat kinase 2. Last modified on 23/07/2020. Accessed on 28/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2059.