Top ▲

leucine rich repeat kinase 2

Click here for help

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

Contents:

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
Alphafold Q5S007 (Hs), Q5S006 (Mm)
BRENDA 2.7.11.1
CATH/Gene3D 1.25.40.20, 2.130.10.10, 3.80.10.10, 1.25.10.10
ChEMBL Target CHEMBL1075104 (Hs), CHEMBL2010622 (Mm)
Ensembl Gene ENSG00000188906 (Hs), ENSMUSG00000036273 (Mm), ENSRNOG00000004048 (Rn)
Entrez Gene 120892 (Hs), 66725 (Mm), 300160 (Rn)
Human Protein Atlas ENSG00000188906 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:120892 (Hs), mmu:66725 (Mm), rno:300160 (Rn)
OMIM 609007 (Hs)
Orphanet ORPHA123301 (Hs)
Pharos Q5S007 (Hs)
RefSeq Nucleotide NM_198578 (Hs), NM_025730 (Mm), NM_001191789 (Rn)
RefSeq Protein NP_940980 (Hs), NP_080006 (Mm), NP_001178718 (Rn)
SynPHARM 81932 (in complex with PF-06454589)
UniProtKB Q5S007 (Hs), Q5S006 (Mm)
Wikipedia LRRK2 (Hs)
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:  7
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:  13
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 Ligand has a PDB structure Hs Inhibition 9.1 pKi 9
⤷ pKi 9.1 (Ki 7x10-10 M) [9]
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 9
⤷ pKi 9.0 (Ki 1x10-9 M) [9]
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 5
⤷ pKi 8.5 (Ki 3x10-9 M) [5]
LRRK2-IN-1 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.2 pKi 14
⤷ pKi 8.2 (Ki 6x10-9 M) [14]
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 4
⤷ pKi 6.6 (Ki 2.478x10-7 M) [4]
TTT-3002 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pIC50 21
⤷ pIC50 9.1 (IC50 7x10-10 M) [21]
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 17
⤷ pIC50 9.0 (IC50 1x10-9 M) [17]
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 13
⤷ pIC50 8.5 (IC50 3x10-9 M) [13]
Description: Biochemical assay using Invitrogen's Lantha Screen technology.
MLI-2 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.2 pIC50 18
⤷ pIC50 8.2 (IC50 6.4x10-9 M) [18]
Description: Determined in a biochemical assay at physiologically relevant ATP concentration (5mM) to mimic cellular conditions.
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 9
⤷ pIC50 8.1 (IC50 9x10-9 M) [9]
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 12
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [12]
PF-06454589 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.9 pIC50 13
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [13]
LRRK2-IN-1 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.9 pIC50 8
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [8]
Description: With 0.1 mM ATP in the assay.
HG-10-102-01 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 – 7.9 pIC50 16
⤷ pIC50 7.9 (IC50 1.24x10-8 M) [16]
Description: Inhibition of WT hLRRK2 in vitro
pIC50 7.6 (IC50 2.43x10-8 M) [16]
Description: Inhibition of LRRK2G2019S in vitro
GNE-9605 Small molecule or natural product Primary target of this compound Hs Inhibition 7.7 pIC50 9
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [9]
JAK3 inhibitor VI Small molecule or natural product Hs Inhibition 7.7 pIC50
⤷ pIC50 7.7 (IC50 2.2x10-8 M)
XMD-12 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 15
⤷ pIC50 7.5 (IC50 3x10-8 M) [15]
BOS172722 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 20
⤷ pIC50 7.3 (IC50 4.8x10-8 M) [20]
EB-42486 Small molecule or natural product Hs Inhibition 6.0 – 8.5 pIC50 11
⤷ pIC50 8.5 (IC50 3.1x10-9 M) [11]
Description: Inhibition of LRRK2 with G2019S mutation
pIC50 6.0 (IC50 1.06x10-6 M) [11]
Description: Inhibition of wild type LRRK2
NIK inhibitor 12f Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.0 pIC50 22
⤷ pIC50 7.0 (IC50 9.46x10-8 M) [22]
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 Ligand has a PDB structure Hs Inhibition 5.2 pIC50 10
⤷ pIC50 5.2 (IC50 6.97x10-6 M) [10]
Description: Determined in a LRRK2 ADAPTA kinase assay.
XL01126 Small molecule or natural product Hs Inhibition - -
⤷
Description: This compound is a PROTAC degrader
Inhibitor Comments
EB-42168 (ESCAPE Bio; structure not disclosed as of Aug 2021) is a LRRK2G2019S-selective inhibitor that is one of the compounds in Garofalo et al. (2020) [11]. It was designed to selectively target the pathogenic LRRK2G2019S variant that increases the risk for developing Parkinson's disease, whilst sparing wild-type LRRK2 activity [3].
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: 6,19
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 Ligand has a PDB structure 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 Ligand has a PDB structure 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 2 GO processes
GO:0006897 endocytosis IMP
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:0032760 positive regulation of tumor necrosis factor production 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

Show »

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. Bright JM, Carlisle HJ, Toda AMA, Murphy M, Molitor TP, Wren P, Andruska KM, Liu E, Barlow C. (2021) Differential Inhibition of LRRK2 in Parkinson's Disease Patient Blood by a G2019S Selective LRRK2 Inhibitor. Mov Disord, 36 (6): 1362-1371. [PMID:33836114]

4. 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]

5. 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]

6. 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]

7. 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 USA, 105 (5): 1499-504. [PMID:18230735]

8. 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]

9. 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]

10. 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]

11. Garofalo AW, Bright J, De Lombaert S, Toda AMA, Zobel K, Andreotti D, Beato C, Bernardi S, Budassi F, Caberlotto L et al.. (2020) Selective Inhibitors of G2019S-LRRK2 Kinase Activity. J Med Chem, 63 (23): 14821-14839. [PMID:33197196]

12. 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]

13. 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]

14. 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]

15. Kwiatkowski N, Deng X, Wang J, Tan L, Villa F, Santaguida S, Huang HC, Mitchison T, Musacchio A, Gray N. (2012) Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen. ACS Chem Biol, 7 (1): 185-96. [PMID:21992004]

16. Liu X, Kalogeropulou K, Domingos S, Makukhin N, Nirujogi R, Singh F, Shpiro N, Saalfrank A, Sammler E, Ganley I et al.. (2022) Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Oral bioavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2). chemrxiv, Preprint. DOI: 10.26434/chemrxiv-2022-4gzm0

17. 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]

18. Scott JD, DeMong DE, Greshock TJ, Basu K, Dai X, Harris J, Hruza A, Li SW, Lin SI, Liu H et al.. (2017) Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity. J Med Chem, 60 (7): 2983-2992. [PMID:28245354]

19. 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]

20. Woodward HL, Innocenti P, Cheung KJ, Hayes A, Roberts J, Henley AT, Faisal A, Mak GW, Box G, Westwood IM et al.. (2018) Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722). J Med Chem, 61 (18): 8226-8240. [PMID:30199249]

21. 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]

22. 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 06/06/2023. Accessed on 01/10/2023. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2059.