LRRK2

Summary

LRRK2 (leucine rich repeat kinase 2, HGNC:18618) is a protein-coding gene on chromosome 12q12, encoding Leucine-rich repeat serine/threonine-protein kinase 2 (Q5S007). Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking.

This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8.

Source: NCBI Gene 120892 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 30
• Clinical variants (ClinVar): 4,043 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 60
• Druggable target: yes — 42 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_198578

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18618
Approved symbol	LRRK2
Name	leucine rich repeat kinase 2
Location	12q12
Locus type	gene with protein product
Status	Approved
Aliases	ROCO2, DKFZp434H2111, FLJ45829, RIPK7
Ensembl gene	ENSG00000188906
Ensembl biotype	protein_coding
OMIM	609007
Entrez	120892

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 nonsense_mediated_decay, 7 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000298910, ENST00000343742, ENST00000416796, ENST00000430804, ENST00000474202, ENST00000479187, ENST00000481256, ENST00000636518, ENST00000644108, ENST00000679360, ENST00000679532, ENST00000679683, ENST00000680018, ENST00000680235, ENST00000680422, ENST00000680425, ENST00000680453, ENST00000680790, ENST00000681136, ENST00000681696, ENST00000681773, ENST00000950031

RefSeq mRNA: 1 — MANE Select: NM_198578 NM_198578

CCDS: CCDS31774

Canonical transcript exons

ENST00000298910 — 51 exons

Exon	Start	End
ENSE00001182762	40367644	40369285
ENSE00001364454	40294845	40294914
ENSE00001364875	40295427	40295644
ENSE00001365419	40283875	40284133
ENSE00001365484	40274583	40274727
ENSE00001367134	40259480	40259604
ENSE00001373174	40287351	40287539
ENSE00001374565	40298243	40298493
ENSE00001374694	40257248	40257377
ENSE00001378233	40263789	40263901
ENSE00001378687	40277888	40278016
ENSE00001379815	40293545	40293663
ENSE00001382909	40278091	40278261
ENSE00001387519	40274854	40274993
ENSE00001597461	40251465	40251544
ENSE00001599015	40252910	40253016
ENSE00001619675	40249826	40249945
ENSE00001635586	40251232	40251374
ENSE00001649052	40232274	40232383
ENSE00001649709	40235626	40235714
ENSE00001727339	40240483	40240617
ENSE00001736708	40237969	40238103
ENSE00001781025	40243550	40243681
ENSE00001860962	40224997	40225282
ENSE00003468154	40323160	40323306
ENSE00003468457	40346753	40346923
ENSE00003476749	40303948	40304134
ENSE00003489241	40367006	40367077
ENSE00003492804	40328360	40328460
ENSE00003496760	40308467	40308696
ENSE00003508420	40310431	40310649
ENSE00003509533	40309106	40309233
ENSE00003511943	40356115	40356187
ENSE00003521951	40319988	40320175
ENSE00003541694	40334967	40335157
ENSE00003551873	40364842	40365050
ENSE00003553579	40351539	40351733
ENSE00003565286	40348409	40348509
ENSE00003568150	40322319	40322510
ENSE00003579735	40321034	40321188
ENSE00003581684	40315212	40315300
ENSE00003603703	40359260	40359444
ENSE00003605121	40299109	40299257
ENSE00003610102	40354299	40354492
ENSE00003621327	40363402	40363554
ENSE00003622781	40313972	40314173
ENSE00003635411	40322035	40322181
ENSE00003635610	40225555	40225640
ENSE00003643319	40302789	40302882
ENSE00003681812	40340294	40340454
ENSE00003691970	40305785	40305966

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 97.17.

FANTOM5 (CAGE): breadth broad, TPM avg 6.2507 / max 882.0565, expressed in 687 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125037	3.9127	484
125038	1.0061	270
125039	0.3517	124
125035	0.2776	136
125045	0.1734	84
125034	0.1365	68
125040	0.1045	46
125036	0.1006	40
125041	0.0870	39
125042	0.0827	40

Top tissues by expression

246 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.17	gold quality
monocyte	CL:0000576	97.06	gold quality
leukocyte	CL:0000738	96.79	gold quality
lower lobe of lung	UBERON:0008949	96.43	gold quality
blood	UBERON:0000178	94.52	gold quality
upper lobe of lung	UBERON:0008948	93.03	gold quality
upper lobe of left lung	UBERON:0008952	92.77	gold quality
right lung	UBERON:0002167	92.40	gold quality
lung	UBERON:0002048	91.86	gold quality
calcaneal tendon	UBERON:0003701	91.42	gold quality
granulocyte	CL:0000094	90.15	gold quality
oviduct epithelium	UBERON:0004804	90.06	gold quality
metanephros cortex	UBERON:0010533	88.79	gold quality
visceral pleura	UBERON:0002401	88.44	gold quality
adrenal tissue	UBERON:0018303	87.81	gold quality
trabecular bone tissue	UBERON:0002483	86.85	gold quality
bone marrow cell	CL:0002092	86.64	gold quality
kidney epithelium	UBERON:0004819	86.24	silver quality
bone marrow	UBERON:0002371	86.03	gold quality
vermiform appendix	UBERON:0001154	85.16	gold quality
descending thoracic aorta	UBERON:0002345	84.56	gold quality
tibial nerve	UBERON:0001323	84.00	gold quality
mucosa of stomach	UBERON:0001199	83.27	gold quality
spleen	UBERON:0002106	83.27	gold quality
adult mammalian kidney	UBERON:0000082	83.13	gold quality
metanephros	UBERON:0000081	83.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.63	gold quality
epithelial cell of pancreas	CL:0000083	82.62	gold quality
thoracic aorta	UBERON:0001515	82.58	gold quality
vagina	UBERON:0000996	82.57	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	25299.14
E-ANND-2	yes	7274.70
E-HCAD-1	yes	99.97
E-ANND-3	yes	27.78
E-CURD-112	yes	27.31
E-GEOD-130148	yes	18.81
E-MTAB-9067	yes	14.43
E-MTAB-9801	yes	7.57
E-GEOD-124858	no	208.71
E-CURD-11	no	144.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CADPS2	Activation

Upstream regulators (CollecTRI, top): NR3C1

miRNA regulators (miRDB)

138 targeting LRRK2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1 (PMID:11891824)
• PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism (PMID:14691730)
• missense mutations segregating with PARK8-linked Parkinson’s disease (PMID:15541308)
• LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism (PMID:15541309)
• a single LRRK2 mutation (a novel mutation (Gly2019 ser) causes Parkinson’s disease in 5% of individuals with familial disease (PMID:15680455)
• confirm association of LRRK2 heterozygous mutation (Gly2019 ser)with neurodegeneration, and identify a common mutation associated with dominantly inherited Parkinson’s disease. (PMID:15680456)
• LRRK2 gene heterozygous mutation (Gly2019 ser) CAUSE dominantly inherited Parkinson’s disease. (PMID:15680457)
• our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis. (PMID:15726496)
• we describe two families with autosomal dominant Parkinson’s disease caused by a LRRK2 G2019S mutation. (PMID:15732108)
• missense mutation in the kinase domain of the LRRK2 gene in members with autosomal dominant Parkinson’s disease (PMID:15880653)
• Missense mutation Gly2019Ser of LRRK2 gene is associated of parkinson disease. (PMID:15884041)
• the G2019S mutation of LRRK2 is responsible for 1 to 2% of Parkinson disease patients in a North American population (PMID:15929036)
• The LRRK2 mutation as a cause of Parkinson’s disease. (PMID:15955578)
• This longitudinal analysis provides preliminary evidence that changes in platelet MAO activity and cholesterol, which may reflect changes in central serotonergic activity are associated with attention deficit in adolescents. (PMID:15955629)
• A healthy octogenarian shows that a G2019S mutation carrier can live to old age free parkinson disease. (PMID:16001413)
• We screened for the most common LRRK 2 mutation in a series of patients with Parkinson’s Disease, Alzheimer’s disease, Progressive Supranuclear Palsy, Multiple System Atrophy and frontotemporal dementia, as well as in neurologically normal controls. (PMID:16102903)
• It can be concluded that the G 2019 S and I 2020 T mutations in exon 41 of LRRK 2 gene are rare causes of Parkinson disease in a Polish population. (PMID:16115731)
• analysis of a common founder effect in the G2019S mutation of LRRK2 dating from the 13th century (PMID:16145815)
• G2019S dardarin substitution is a common cause of Parkinson’s disease in a Portuguese cohort. (PMID:16149095)
• The common coding variations in the LRRK2 gene neither constitute strong PD risk factors nor modify the age at onset; however, the possibility of a modest risk effect remains to be assessed in large datasets. (PMID:16157901)
• Thus LRRK2 mutations only rarely cause idiopathic PD. (PMID:16157908)
• These data confirm the important contribution of LRRK2 to PD susceptibility in a clinic-based population. (PMID:16157909)
• Lrrk2 pathogenic substitutions may have a role in Parkinson’s disease (PMID:16172858)
• LRRK2 mutations appear to be a common cause of autosomal dominant PD, particularly in North Africa. (PMID:16240353)
• Sequence analysis of 29 exons coding for functional domains of LRRK2 in 160 nondominant Parkinson disease patients was performed. Two novel variants (R1067Q and IVS33 + 6 T>A) were found, which are likely to be pathogenic in five patients. (PMID:16247070)
• LRRK2 G2019S is the single most common pathogenic mutation linked to neurodegenerative disease to date. (PMID:16250030)
• We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson’s disease risk (PMID:16254973)
• The first evidence that common genetic variation within LRRK2 contributes to the risk of sporadic PD in the Chinese population was provided. (PMID:16269443)
• results suggest a gain-of-function mechanism for LRRK2-linked disease with a central role for kinase activity in the development of Parkinson disease (PMID:16269541)
• the G2019S mutation in LRRK2 is the most common genetic determinant of Parkinson’s disease identified so far (PMID:16272257)
• examination of mutations responsible for Parkinson disease (PMID:16275903)
• The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. (PMID:16321986)
• LRRK2 mutations are frequent in autosomal dominant Parkinson’s disease, and they cluster in the C-terminal half of the encoded protein (PMID:16333314)
• LRRK2 may be involved in a pathogenic pathway with other parkinson’s disease (PD) -related proteins such as parkin, which may help illuminate both familial and sporadic PD (PMID:16352719)
• the frequency of the G2019S mutation in this gene is remarkably high in North African Arabs with familial Parkinsons’s disease (PMID:16436781)
• The G2019S mutation appears to be an important cause of both familial and sporadic Parkinson’s disease in a group of Ashkenazi Jewish subjects. (PMID:16436782)
• Lrrk2 G2019S was observed in approximately 2% (n = 8) of Parkinson’s disease/Lewy body disease cases (n = 405). (PMID:16437559)
• This is the first comprehensive analysis of common variability within LRRK2 as a risk factor for Parkinson’s disease (PD). (PMID:16467219)
• The extreme rarity of the G2019S mutation in Taiwan in Parkinson disease suggests the occurrence of this mutation resulted from a common European founder (PMID:16511860)
• The G2019S mutation frequency in PD patients from northeast Spain is similar to that reported in other European regions. The R1441G mutation is very uncommon in Catalonia. (PMID:16533964)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrk2	ENSDARG00000006169
mus_musculus	Lrrk2	ENSMUSG00000036273
rattus_norvegicus	Lrrk2	ENSRNOG00000004048

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541)

Protein

Protein identifiers

Leucine-rich repeat serine/threonine-protein kinase 2 — Q5S007 (reviewed: Q5S007)

Alternative names: Dardarin

All UniProt accessions (15): A0A1B0GUQ3, A0A2R8Y4F8, A0A7P0T8S1, A0A7P0T8T1, A0A7P0T8T5, A0A7P0T9F8, A0A7P0TAJ2, A0A7P0TAW6, A0A7P0TB00, A0A7P0Z468, A0A7P0Z4D9, C9JBF0, E9PC85, Q5S007, H7C3B6

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking. Is a key regulator of RAB GTPases by regulating the GTP/GDP exchange and interaction partners of RABs through phosphorylation. Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB29, RAB35, and RAB43. Regulates the RAB3IP-catalyzed GDP/GTP exchange for RAB8A through the phosphorylation of ‘Thr-72’ on RAB8A. Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by phosphorylating ‘Thr-72’ on RAB8A. Regulates primary ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the brain. Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. Plays an important role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Phosphorylates PRDX3. By phosphorylating APP on ‘Thr-743’, which promotes the production and the nuclear translocation of the APP intracellular domain (AICD), regulates dopaminergic neuron apoptosis. Acts as a positive regulator of innate immunity by mediating phosphorylation of RIPK2 downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation. Independent of its kinase activity, inhibits the proteasomal degradation of MAPT, thus promoting MAPT oligomerization and secretion. In addition, has GTPase activity via its Roc domain which regulates LRRK2 kinase activity. Recruited by RAB29/RAB7L1 to overloaded lysosomes where it phosphorylates and stabilizes RAB8A and RAB10 which promote lysosomal content release and suppress lysosomal enlargement through the EHBP1 and EHBP1L1 effector proteins.

Subunit / interactions. Homodimer. Homotetramer; when activated by GTP-bound RAB29. Interacts with PRKN, PRDX3, and TPCN2. Interacts with VPS35. Interacts (via N-terminus) with RAB29; this interaction is direct and stimulates kinase activity. Interacts (via ROC domain) with SEC16A. Interacts with APP; interaction promotes phosphorylation of ‘Thr-743’ of APP. Interacts with MAPT. Interacts with RAB8A, RAB10, and RAB12. Interacts (via N-terminus) with RAB32. Interacts with YWHAG; this interaction is dependent on phosphorylation of Ser-910 and either Ser-935 or Ser-1444. Interacts with SFN; this interaction is dependent on phosphorylation of Ser-910 and/or Ser-935.

Subcellular location. Cytoplasmic vesicle. Perikaryon. Golgi apparatus membrane. Cell projection. Axon. Dendrite. Endoplasmic reticulum membrane. Secretory vesicle. Synaptic vesicle membrane. Endosome. Lysosome. Mitochondrion outer membrane. Cytoplasm. Cytoskeleton. Phagosome.

Tissue specificity. Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). Expressed in neutrophils (at protein level). Expressed in the brain. Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas.

Post-translational modifications. Autophosphorylated at Ser-1292; autophosphorylation is stimulated by RAB29. Phosphorylation of Ser-910 and either Ser-935 or Ser-1444 facilitates interaction with YWHAG. Phosphorylation of Ser-910 and/or Ser-935 facilitates interaction with SFN. Ubiquitinated by TRIM1; undergoes ‘Lys-48’-linked polyubiquitination leading to proteasomal degradation.

Disease relevance. Parkinson disease 8 (PARK8) [MIM:607060] A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Kinase activity is regulated by the GTPase activity of the ROC domain. GTP-bound LRRK2 kinase activity is stimulated by RAB29. Phosphorylation of RAB10 ‘Thr-73’ is stimulated by RAB29 and RAB32. Inhibited by small molecule inhibitor MLi-2.

Domain organisation. The seven-bladed WD repeat region is critical for synaptic vesicle trafficking and mediates interaction with multiple vesicle-associated presynaptic proteins. It also mediates homodimerization and regulates kinase activity. The COR domain mediates homodimerization; it also mediates homotetramerization via interaction with the protein kinase domain. The Roc domain mediates homodimerization and regulates kinase activity.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

RefSeq proteins (1): NP_940980* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR005225	Small_GTP-bd	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020859	ROC	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032171	COR-A	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR051420	Ser_Thr_Kinases_DiverseReg	Family
IPR056593	ANK_LRRK2	Domain
IPR056597	ARM_LRRK2	Domain
IPR056602	Beta-prop_LRRK2	Domain
IPR057263	COR-B	Domain

Pfam: PF00069, PF08477, PF13855, PF16095, PF23744, PF23745, PF23748, PF25497

Catalyzed reactions (Rhea), 3 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (336 total): strand 91, helix 79, sequence variant 58, mutagenesis site 34, turn 21, repeat 20, binding site 19, modified residue 6, domain 3, chain 1, sequence conflict 1, region of interest 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

44 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5MY9	X-RAY DIFFRACTION	1.33
5MYC	X-RAY DIFFRACTION	1.46
6OJF	X-RAY DIFFRACTION	1.6
6OJE	X-RAY DIFFRACTION	1.95
6XAF	X-RAY DIFFRACTION	1.97
2ZEJ	X-RAY DIFFRACTION	2
9C76	X-RAY DIFFRACTION	2.3
3D6T	X-RAY DIFFRACTION	2.43
6DLO	X-RAY DIFFRACTION	2.7
8TZC	ELECTRON MICROSCOPY	2.7
8TZG	ELECTRON MICROSCOPY	2.7
8TZE	ELECTRON MICROSCOPY	2.9
8TYQ	ELECTRON MICROSCOPY	2.99
8TXZ	ELECTRON MICROSCOPY	3.05
7LI4	ELECTRON MICROSCOPY	3.1
8TZB	ELECTRON MICROSCOPY	3.1
9DMI	ELECTRON MICROSCOPY	3.35
8TZF	ELECTRON MICROSCOPY	3.4
8U8A	ELECTRON MICROSCOPY	3.4
6VP6	ELECTRON MICROSCOPY	3.47
8FO9	ELECTRON MICROSCOPY	3.48
6VNO	ELECTRON MICROSCOPY	3.5
6VP7	ELECTRON MICROSCOPY	3.5
6VP8	ELECTRON MICROSCOPY	3.5
7LHT	ELECTRON MICROSCOPY	3.5
8FO7	ELECTRON MICROSCOPY	3.52
8U7L	ELECTRON MICROSCOPY	3.6
7LHW	ELECTRON MICROSCOPY	3.7
8U1B	ELECTRON MICROSCOPY	3.7
8U8B	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5S007-F1	77.64	0.13

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1994 (proton acceptor)

Ligand- & substrate-binding residues (19): 1341–1348; 1885; 1887; 1888; 1891; 1893; 1904; 1906; 1947; 1948; 1950; 1954 …

Post-translational modifications (6): 910, 935, 955, 973, 1292, 1444

Mutagenesis-validated functional residues (34):

Position	Phenotype
399	reduces membrane localization and abolishes interaction with rab29/rab7l1. impairs rab29-stimulated kinase activity on r
403	reduces membrane localization and abolishes interaction with rab29/rab7l1. impairs rab29-stimulated kinase activity on r
727	decreased kinase activity. loss of rab29-mediated activation and autophosphorylation of s-910, s-935, s-955, s-973 and s
728	decreased kinase activity. loss of rab29-mediated activation and autophosphorylation of s-910, s-935, s-955, s-973 and s
729	decreased kinase activity. loss of rab29-mediated activation and autophosphorylation of s-910, s-935, s-955, s-973 and s
760	decreased kinase activity and loss of rab29-mediated activation.
761	decreased kinase activity and loss of rab29-mediated activation.
762	decreased kinase activity and loss of rab29-mediated activation.
789	no effect on kinase activity and rab29-mediated activation.
790	no effect on kinase activity and rab29-mediated activation.
791	no effect on kinase activity and rab29-mediated activation.
1343	decreased kinase activity; when associated with q-1398.
1347	gtpase-dead mutant. loss of interaction with sec16a and impaired ability to recruit sec16a to endoplasmic reticulum exit
1348	loss of gtp binding. inhibits autophosphorylation and rab10 phosphorylation; when associated with g-1441, c-1699, or s-2
1398	decreased kinase activity; when associated with g-1343.
1441	decreased membrane association when associated with d-727, d-728, or d-729. inhibits autophosphorylation and rab10 phosp
1588	impairs rab29-stimulated kinase activity on rab10, rab29 and lrrk2.
1699	decreased membrane association when associated with d-727, d-728, or d-729. inhibits autophosphorylation and rab10 phosp
1710	impairs rab29-stimulated kinase activity on rab10, rab29 and lrrk2.
1791	impairs rab29-stimulated kinase activity on rab10, rab29 and lrrk2.
1906	loss of kinase activity. decreases proteasomal degradation of mapt; when associated with n-1994 and a-2017.
1994	loss of kinase activity.
1994	loss of kinase activity. no loss of interaction with sec16a and no loss of ability to recruit sec16a to endoplasmic reti
2017	loss of kinase activity. decreases proteasomal degradation of mapt; when associated with a-1906 and n-1994. loss of phos
2019	decreased membrane association when associated with d-727, d-728, or d-729. inhibits autophosphorylation and rab10 phosp

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8857538	PTK6 promotes HIF1A stabilization
R-HSA-162582	Signal Transduction
R-HSA-8848021	Signaling by PTK6
R-HSA-9006927	Signaling by Non-Receptor Tyrosine Kinases

MSigDB gene sets: 769 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_CELL_MATURATION, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_LYSOSOMAL_TRANSPORT, GOBP_BEHAVIOR, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION

GO Biological Process (106): MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), protein import into nucleus (GO:0006606), endocytosis (GO:0006897), autophagy (GO:0006914), response to oxidative stress (GO:0006979), mitochondrion organization (GO:0007005), endoplasmic reticulum organization (GO:0007029), Golgi organization (GO:0007030), lysosome organization (GO:0007040), JNK cascade (GO:0007254), Rho protein signal transduction (GO:0007266), spermatogenesis (GO:0007283), neuromuscular junction development (GO:0007528), intracellular protein localization (GO:0008104), determination of adult lifespan (GO:0008340), cellular response to starvation (GO:0009267), regulation of autophagy (GO:0010506), positive regulation of autophagy (GO:0010508), negative regulation of protein processing (GO:0010955), negative regulation of neuron projection development (GO:0010977), regulation of neuron maturation (GO:0014041), negative regulation of macroautophagy (GO:0016242), calcium-mediated signaling (GO:0019722), striatum development (GO:0021756), olfactory bulb development (GO:0021772), tangential migration from the subventricular zone to the olfactory bulb (GO:0022028), regulation of cell projection organization (GO:0031344), positive regulation of protein ubiquitination (GO:0031398), regulation of protein stability (GO:0031647), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), positive regulation of tumor necrosis factor production (GO:0032760), negative regulation of GTPase activity (GO:0034260), cellular response to oxidative stress (GO:0034599), cellular response to reactive oxygen species (GO:0034614), regulation of SNARE complex assembly (GO:0035542), intracellular signal transduction (GO:0035556), regulation of kidney size (GO:0035564), exploration behavior (GO:0035640), locomotory exploration behavior (GO:0035641)

GO Molecular Function (31): SNARE binding (GO:0000149), magnesium ion binding (GO:0000287), actin binding (GO:0003779), GTPase activity (GO:0003924), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), JUN kinase kinase kinase activity (GO:0004706), MAP kinase kinase kinase activity (GO:0004709), GTPase activator activity (GO:0005096), ATP binding (GO:0005524), GTP binding (GO:0005525), microtubule binding (GO:0008017), tubulin binding (GO:0015631), kinase activity (GO:0016301), syntaxin-1 binding (GO:0017075), signaling receptor complex adaptor activity (GO:0030159), clathrin binding (GO:0030276), small GTPase binding (GO:0031267), GTP-dependent protein kinase activity (GO:0034211), peroxidase inhibitor activity (GO:0036479), co-receptor binding (GO:0039706), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), transmembrane transporter binding (GO:0044325), protein kinase A binding (GO:0051018), protein serine kinase activity (GO:0106310), beta-catenin destruction complex binding (GO:1904713), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

GO Cellular Component (52): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), Golgi-associated vesicle (GO:0005798), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), microvillus (GO:0005902), axon (GO:0030424), dendrite (GO:0030425), growth cone (GO:0030426), synaptic vesicle membrane (GO:0030672), cytoplasmic vesicle (GO:0031410), nuclear membrane (GO:0031965), mitochondrial membrane (GO:0031966), cytoplasmic side of mitochondrial outer membrane (GO:0032473), dendrite cytoplasm (GO:0032839), ciliary basal body (GO:0036064), neuron projection (GO:0043005), neuronal cell body (GO:0043025), terminal bouton (GO:0043195), perikaryon (GO:0043204), amphisome (GO:0044753), autolysosome (GO:0044754), phagocytic vesicle (GO:0045335), extracellular exosome (GO:0070062), endoplasmic reticulum exit site (GO:0070971), Lewy body (GO:0097413), multivesicular body, internal vesicle (GO:0097487), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by PTK6	1
Signaling by Non-Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
organelle organization	3
cellular anatomical structure	3
intracellular membrane-bounded organelle	3
endomembrane system	3
endomembrane system organization	2
MAPK cascade	2
autophagy	2
protein binding	2
cytoskeletal protein binding	2
protein serine/threonine kinase activity	2
purine ribonucleoside triphosphate binding	2
mitochondrial membrane	2
cytoplasmic vesicle	2
neuron projection	2
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
response to stress	1
lytic vacuole organization	1
small GTPase-mediated signal transduction	1
developmental process involved in reproduction	1
male gamete generation	1
synapse organization	1
macromolecule localization	1
multicellular organismal process	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1

Protein interactions and networks

STRING

6024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRK2	RAB29	O14966	989
LRRK2	PARK7	Q99497	984
LRRK2	PRKN	O60260	981
LRRK2	SNCA	P37840	973
LRRK2	PINK1	Q9BXM7	955
LRRK2	GAK	O14976	953
LRRK2	GBA1	P04062	922
LRRK2	VPS35	Q96QK1	863
LRRK2	ATP13A2	Q9NQ11	844
LRRK2	MAPT	P10636	826
LRRK2	SH3GL3	Q99963	822
LRRK2	FBXO7	Q9Y3I1	808
LRRK2	MFN1	Q8IWA4	802
LRRK2	UCHL1	P09936	785
LRRK2	RHOT1	Q8IXI2	781

IntAct

882 interactions, top by confidence:

A	B	Type	Score
LRRK2	LRRK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.990
LRRK2	LRRK2	psi-mi:“MI:1126”(self interaction)	0.990
LRRK2	LRRK2	psi-mi:“MI:0915”(physical association)	0.990
LRRK2	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.990
	LRRK2	psi-mi:“MI:0915”(physical association)	0.980
	LRRK2	psi-mi:“MI:0883”(gtpase reaction)	0.980
LRRK2	MSN	psi-mi:“MI:0217”(phosphorylation reaction)	0.960
LRRK2	DNM1L	psi-mi:“MI:0915”(physical association)	0.910
YWHAG	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.860

BioGRID (722): LRRK1 (Affinity Capture-Western), LRRK2 (Affinity Capture-Western), BAX (Affinity Capture-Western), EPRS (Affinity Capture-MS), SRPK1 (Affinity Capture-MS), HSPA9 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), ATRX (Affinity Capture-MS), TK1 (Affinity Capture-MS), CHD1L (Affinity Capture-MS), C17orf53 (Affinity Capture-MS), HERC2 (Affinity Capture-MS), NEURL4 (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), CDC37 (Affinity Capture-MS)

ESM2 similar proteins: A0A2H5Q1B8, A5HEI1, A6NKT7, A9JR78, B0CM26, B0JZ65, B0R160, B0VXE6, D1KF50, E7BQV0, F4I240, F4JHT3, F4JS25, F4JY37, F4KEY9, F6S215, O23463, O65020, O74447, P82805, P82872, P93002, P97313, P97357, Q03569, Q3B7U2, Q57ZB2, Q5ICL9, Q5S006, Q5S007, Q6GM71, Q6Q4D0, Q7KLI1, Q7Z3J3, Q8BH53, Q8C3Y4, Q8CDM1, Q8H1U4, Q8L746, Q8LNZ2

Diamond homologs: A2QHV0, A2XQD3, A6QGC0, A7J1T0, A7J1T2, A7MBB4, A8R7E6, A8X775, C0LGG7, D7UPN3, O04534, O22833, O22834, O43283, O64556, O64768, O64770, O64771, O64776, O64777, O64778, O64780, O65468, O65482, O81832, P00536, P00537, P00538, P00539, P00540, P07331, P08631, P10421, P10650, P10741, P12965, P32593, P50118, P87347, P93604

SIGNOR signaling

53 interactions.

A	Effect	B	Mechanism
LRRK2	“up-regulates activity”	MSN	phosphorylation
LRRK2	up-regulates	LRRK2	phosphorylation
ARHGEF7	up-regulates	LRRK2	binding
LRRK2	up-regulates	ARHGEF7	phosphorylation
LRRK2	up-regulates	AKT1	phosphorylation
LRRK2	down-regulates	LRRK2	phosphorylation
LRRK2	unknown	LRRK2	phosphorylation
LRRK2	down-regulates	SH3GL1	phosphorylation
LRRK2	down-regulates	SH3GL2	phosphorylation
LRRK2	down-regulates	MAPT	phosphorylation
ARFGAP1	up-regulates	LRRK2	binding
LRRK2	down-regulates	ARFGAP1	phosphorylation
LRRK2	up-regulates	DVL3	binding
LRRK2	down-regulates	SNAPIN	phosphorylation
LRRK2	up-regulates	AKT	phosphorylation
LRRK2	up-regulates	Autophagy
LRRK2	“down-regulates activity”	SNCA	phosphorylation
LRRK2	“down-regulates activity”	RAB10	phosphorylation
LRRK2	“down-regulates activity”	PRDX3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAB geranylgeranylation	8	20.7×	2e-06
RAB GEFs exchange GTP for GDP on RABs	7	13.0×	2e-04
COPII-mediated vesicle transport	5	12.2×	3e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	11.5×	3e-03
SARS-CoV-2-host interactions	5	8.9×	6e-03
Cell Cycle Checkpoints	6	7.9×	4e-03
SARS-CoV-2 Infection	6	7.2×	5e-03
RHO GTPase Effectors	7	7.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical Wnt signaling pathway	7	10.8×	9e-04
Golgi organization	8	10.7×	4e-04
endocytosis	9	8.6×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

4043 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	2378
Likely benign	1304
Benign	170

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1936	NM_198578.4(LRRK2):c.4321C>G (p.Arg1441Gly)	Pathogenic
1937	NM_198578.4(LRRK2):c.5096A>G (p.Tyr1699Cys)	Pathogenic
1938	NM_198578.4(LRRK2):c.4321C>T (p.Arg1441Cys)	Pathogenic
1939	NM_198578.4(LRRK2):c.3364A>G (p.Ile1122Val)	Pathogenic
1941	NM_198578.4(LRRK2):c.6059T>C (p.Ile2020Thr)	Pathogenic
2572065	NM_198578.4(LRRK2):c.4969C>T (p.Gln1657Ter)	Pathogenic
225276	NM_198578.4(LRRK2):c.4321C>A (p.Arg1441Ser)	Likely pathogenic
3341978	NM_198578.4(LRRK2):c.4318G>C (p.Ala1440Pro)	Likely pathogenic

SpliceAI

7956 predictions. Top by Δscore:

Variant	Effect	Δscore
12:40225262:TGTTC:T	donor_gain	1.0000
12:40225278:GCGCG:G	donor_gain	1.0000
12:40225283:G:A	donor_loss	1.0000
12:40225284:T:A	donor_loss	1.0000
12:40232272:AGGTG:A	acceptor_gain	1.0000
12:40232273:GGTGG:G	acceptor_gain	1.0000
12:40232384:G:GG	donor_gain	1.0000
12:40235618:A:AG	acceptor_gain	1.0000
12:40235619:A:G	acceptor_gain	1.0000
12:40235625:GATT:G	acceptor_gain	1.0000
12:40235710:TTCAG:T	donor_loss	1.0000
12:40235711:TCAG:T	donor_loss	1.0000
12:40235712:CAG:C	donor_loss	1.0000
12:40235713:AGG:A	donor_loss	1.0000
12:40235714:G:GC	donor_loss	1.0000
12:40235715:G:C	donor_loss	1.0000
12:40235716:T:A	donor_loss	1.0000
12:40240475:T:G	acceptor_gain	1.0000
12:40240480:A:AG	acceptor_gain	1.0000
12:40240481:A:G	acceptor_gain	1.0000
12:40240482:G:GC	acceptor_gain	1.0000
12:40240613:TCCTT:T	donor_gain	1.0000
12:40240614:CCTT:C	donor_gain	1.0000
12:40240614:CCTTG:C	donor_loss	1.0000
12:40240615:CTT:C	donor_gain	1.0000
12:40240615:CTTG:C	donor_loss	1.0000
12:40240616:TT:T	donor_gain	1.0000
12:40240616:TTG:T	donor_loss	1.0000
12:40240617:TGTA:T	donor_loss	1.0000
12:40240618:G:GG	donor_gain	1.0000

AlphaMissense

16717 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:40308684:T:A	W1393R	0.999
12:40308684:T:C	W1393R	0.999
12:40321096:G:C	R1693P	0.999
12:40328414:C:A	A1904D	0.999
12:40334968:A:T	E1920V	0.999
12:40340395:A:T	D2017V	0.999
12:40304106:T:C	L1250P	0.998
12:40308517:T:C	L1337P	0.998
12:40308528:G:A	G1341R	0.998
12:40308528:G:C	G1341R	0.998
12:40308529:G:A	G1341E	0.998
12:40310462:T:A	V1450D	0.998
12:40314162:T:C	L1576P	0.998
12:40320115:T:C	L1652P	0.998
12:40321131:T:A	W1705R	0.998
12:40321131:T:C	W1705R	0.998
12:40322088:T:A	W1742R	0.998
12:40322088:T:C	W1742R	0.998
12:40322372:T:A	W1791R	0.998
12:40322372:T:C	W1791R	0.998
12:40328381:T:A	V1893D	0.998
12:40328383:T:G	Y1894D	0.998
12:40328417:T:A	V1905E	0.998
12:40328421:G:C	K1906N	0.998
12:40328421:G:T	K1906N	0.998
12:40328456:G:C	R1918T	0.998
12:40334968:A:C	E1920A	0.998
12:40334971:T:C	L1921P	0.998
12:40340323:G:C	R1993P	0.998
12:40340326:A:C	D1994A	0.998

dbSNP variants (sampled 300 via entrez): RS1000022561 (12:40296423 A>C), RS1000028118 (12:40307533 A>G), RS1000054104 (12:40257876 A>G), RS1000058911 (12:40274236 T>G), RS1000064496 (12:40280851 G>A,T), RS1000072730 (12:40352349 A>G,T), RS1000099362 (12:40308956 C>A,G,T), RS1000106124 (12:40258756 G>A), RS1000180281 (12:40344825 G>C), RS1000224155 (12:40289630 T>C), RS1000232603 (12:40345116 C>G,T), RS1000234623 (12:40255201 C>T), RS1000267177 (12:40254952 A>C), RS1000294117 (12:40321100 A>G), RS1000304551 (12:40239789 T>A)

Disease associations

OMIM: gene MIM:609007 | disease phenotypes: MIM:607060, MIM:609888, MIM:168600, MIM:118100

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease	Definitive	Autosomal dominant
autosomal dominant Parkinson disease 8	Definitive	Autosomal dominant
hereditary late onset Parkinson disease	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Parkinson disease	Definitive	AD

Mondo (10): autosomal dominant Parkinson disease 8 (MONDO:0011764), leprosy, susceptibility to, 1 (MONDO:0012358), Parkinson disease (MONDO:0005180), late-onset Parkinson disease (MONDO:0008199), young-onset Parkinson disease (MONDO:0017279), parkinsonian disorder (MONDO:0021095), vascular parkinsonism (MONDO:0956980), frontotemporal dementia (MONDO:0017276), Klippel-Feil syndrome 1, autosomal dominant (MONDO:0007306), (MONDO:0018466)

Orphanet (6): Hereditary late-onset Parkinson disease (Orphanet:411602), Leprosy (Orphanet:548), Young-onset Parkinson disease (Orphanet:2828), Frontotemporal dementia (Orphanet:282), Isolated Klippel-Feil syndrome (Orphanet:2345), NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000338	Hypomimic face
HP:0000551	Color vision defect
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000744	Low frustration tolerance
HP:0001257	Spasticity
HP:0001268	Mental deterioration
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001824	Weight loss
HP:0002014	Diarrhea
HP:0002015	Dysphagia
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002120	Cerebral cortical atrophy
HP:0002141	Gait imbalance
HP:0002171	Gliosis
HP:0002172	Postural instability

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST000207_11	Crohn’s disease	3.000000e-10
GCST000530_3	Parkinson’s disease	3.000000e-08
GCST000879_43	Crohn’s disease	6.000000e-21
GCST000959_3	Parkinson’s disease	6.000000e-14
GCST001126_8	Parkinson’s disease	2.000000e-28
GCST001445_1	Parkinson’s disease	3.000000e-21
GCST001445_2	Parkinson’s disease	6.000000e-15
GCST001725_24	Inflammatory bowel disease	6.000000e-29
GCST001762_899	Obesity-related traits	5.000000e-06
GCST002455_1	Parkinson’s disease	2.000000e-27
GCST002544_25	Parkinson’s disease	5.000000e-14
GCST002772_20	Leprosy	2.000000e-07
GCST003074_16	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	9.000000e-08
GCST003097_24	Pediatric autoimmune diseases	3.000000e-10
GCST003518_35	Daytime sleep phenotypes	8.000000e-07
GCST003922_3	Parkinson’s disease	8.000000e-12
GCST003984_1	Parkinson’s disease	1.000000e-39
GCST004131_46	Inflammatory bowel disease	3.000000e-15
GCST004132_23	Crohn’s disease	6.000000e-20
GCST004902_5	Parkinson’s disease	1.000000e-19
GCST005537_87	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	4.000000e-17
GCST009325_74	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-20
GCST009325_8	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-28
GCST009325_9	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	4.000000e-148
GCST009512_2	Parkinson’s disease	7.000000e-11
GCST010204_51	Low density lipoprotein cholesterol levels	2.000000e-09
GCST90002395_124	Mean platelet volume	3.000000e-12
GCST90002400_81	Plateletcrit	4.000000e-13
GCST90002401_237	Platelet distribution width	3.000000e-11
GCST90002402_370	Platelet count	1.000000e-20

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005187	C-peptide measurement
EFO:0007707	cerebral amyloid deposition measurement
EFO:0007828	daytime rest measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D057180	Frontotemporal Dementia	C10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
C536887	Klippel Feil syndrome dominant type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1075104 (SINGLE PROTEIN), CHEMBL5465219 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465239 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

42 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 901,190 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2103743	TOFACITINIB CITRATE	4	1,672
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL1879463	DACTOLISIB	3	7,988
CHEMBL226345	ADENINE	3	541,090
CHEMBL2316582	OLVEREMBATINIB	3	353
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL38380	FASUDIL	3	11,953
CHEMBL428690	ALVOCIDIB	3
CHEMBL4297865	ABIVERTINIB	3
CHEMBL483158	ALISERTIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3
CHEMBL1721885	SU-014813	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1976040	ADAVOSERTIB	2

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Leucine-rich repeat kinase (LRRK) family

Most potent curated ligand interactions (24 total), top 24:

Ligand	Action	Affinity	Parameter
TTT-3002	Inhibition	9.15	pIC50
GNE-0877	Inhibition	9.15	pKi
compound 20 [PMID: 30998356]	Inhibition	9.0	pIC50
JH-XII-03-02	Inhibition	9.0	pIC50
GNE-7915	Binding	9.0	pKi
PF-06447475	Inhibition	8.52	pIC50
MLI-2	Inhibition	8.19	pIC50
URMC-099	Inhibition	7.96	pIC50
PF-06454589	Inhibition	7.92	pIC50
LRRK2-IN-1	Inhibition	7.89	pIC50
GNE-9605	Inhibition	7.72	pIC50
JAK3 inhibitor VI	Inhibition	7.66	pIC50
HG-10-102-01	Inhibition	7.61	pIC50
XMD-12	Inhibition	7.52	pIC50
liradasertib	Inhibition	7.52	pIC50
LRRK2 inhibitor 6 [PMID: 40353293]	Inhibition	7.46	pIC50
BOS172722	Inhibition	7.32	pIC50
pelerasertib	Inhibition	7.3	pIC50
NIK inhibitor 12f	Inhibition	7.02	pIC50
EB-42168	Inhibition	6.84	pIC50
NIK SMI1	Inhibition	6.61	pKi
EB-42486	Inhibition	5.97	pIC50
GSK2646264	Inhibition	5.4	pIC50
DCLK1-IN-1	Inhibition	5.16	pIC50

Binding affinities (BindingDB)

1802 measured of 2191 human assays (2191 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(10aR,13aR)- or (10aS,13aS)-3-cyclobutyl-1-methyl-8- (trifluoromethyl)-3,4,10a,11,12,13,13a,14- octahydro-10H-5,9- (azeno)cyclopenta[k]pyrazolo[4,3- b][1]oxa[4,6, 10]triazacyclotridecine	IC50	0.087 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aS,13aS)- or (10aR,13aR)-3-((1R,3S)-3- methoxycyclobutyl)-1-methyl-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.091 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(R)- or (S)-butyl-7-methyl-10- (trifluoromethyl)-1,5,6,7,8,14-hexahydro- 9,13-(azeno)pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecin-3-yl)-2- methylpropanenitrile	IC50	0.093 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
US20250313575, Ex-7.2	IC50	0.093 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(3S,7S)-12-methyl-20-(trifluoromethyl)-5,9-dioxa-2,11,16,18,21-pentazatetracyclo[15.3.1.03,7.010,15]henicosa-1(21),10(15),11,13,17,19-hexaene	IC50	0.098 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aS,13aS)-1-cyclopropyl-3-isopropyl-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.105 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aS,13aS)-3-isopropyl-1-methyl-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.117 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(3S,7S)-14-chloro-20-(trifluoromethyl)-5,9-dioxa-2,13,16,18,21-pentazatetracyclo[15.3.1.03,7.010,15]henicosa-1(21),10(15),11,13,17,19-hexaene	IC50	0.126 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aR,12aR)-8-chloro-1-methyl-3- (trifluoromethyl)- 1,4,10,10a,11,12,12a,13-octahydro- 5,9- (azeno)cyclobuta[k]pyrazolo[3,4- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.135 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
methyl (10aS,13aS)-3-cyclobutyl-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine-1- carboxylate	IC50	0.158 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(1R,2R)- or (1S,2S)-2-((10aS,13aS)-3-cyclobutyl-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecin-1- yl)cyclopropane-1-carbonitrile	IC50	0.17 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
2-((10aS,13aS)-8-chloro-3- isopropyl-10a,11,13a,14-tetrahydro- 10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[3,4- b][1]oxa[4,6,10]triazacyclotridecin- 1(4H)-yl)-2-methylpropanenitrile	IC50	0.174 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aS,13aS)-3-((R)-2,2- difluorocyclopropyl)-1-methyl-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine (10aS,13aS)-3-((S)-2,2- difluorocyclopropyl)-1-methyl-8- (trifluoromethyl)-3,4,10a,11,13a, 14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b|[1]oxa|4,6,10]triazacyclotridecine	IC50	0.195 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(3S,7S)-20-chloro-14-methoxy-5,9-dioxa-2,16,18,21-tetrazatetracyclo[15.3.1.03,7.010,15]henicosa-1(21),10(15),11,13,17,19-hexaene	IC50	0.224 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(3aR,15aR)- or (3aS,15aS)- 11-cyclobutyl-13-methyl-6- (trifluoromethyl)-2,3,3a,4,10,11,15,15a- octahydro-5,9-(azeno)furo[3,2- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.229 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
2-((10aS,12aS)- or 2-((10aR,12aR)-3-cyclobutyl-8- (trifluoromethyl)-3,4,10,10a,11,12,12a,13- octahydro-5,9- (azeno)cyclobuta[k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecin-1-yl)-2- methylpropanenitrile	IC50	0.229 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10R,14R)-4-cyclobutyl-6-methyl-17-(trifluoromethyl)-12-oxa-2,4,5,15,19,20-hexazatetracyclo[14.3.1.03,7.010,14]icosa-1(19),3(7),5,16(20),17-pentaene	IC50	0.24 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aR,12aR)-8-chloro-3-isopropyl- 1-methyl-3,4,10,10a,11,12,12a,13- octahydro-5,9- (metheno)cyclobuta[k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.245 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aR,12aR)-8-chloro-3-isopropyl-1- methyl-3,4,10,10a,11,12,12a,13-octahydro- 5,9-(azeno)cyclobuta[k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.251 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(11aR,14aS) or (11aS,14aR)-3-cyclobutyl-1-methyl-8- (trifluoromethyl)-3,4,10,11,11a,12,14,14a- octahydro-5,9-(azeno)furo[3,4- 1]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.251 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
2-N-(2-methoxy-5-methyl-4-methylsulfonylphenyl)-4-N-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.3 nM	US-9145402: Aminopyrimidine derivatives as LRRK2 modulators
4-N-ethyl-2-N-[3-methyl-1-[2-(2-methylpyrazol-3-yl)propan-2-yl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.3 nM	US-9212173: Pyrazole aminopyrimidine derivatives as LRRK2 modulators
2-N-(6,6-dimethyl-4,7-dihydropyrazolo[5,1-c][1,4]oxazin-3-yl)-4-N-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.3 nM	US-9212186: Bicyclic pyrazole LRRK2 small molecule inhibitors
4-cyclohexyloxy-3-[(E)-2-(1-methylpyrazol-4-yl)ethenyl]-2H-pyrazolo[4,3-c]pyridine	KI	0.3 nM	US-8569281: Compounds and their administration for treating a neurodegenerative disease as well as a method for identifying a compound capable of inhibiting a kinase, such as LRRK
US20250313575, Ex-4.2	IC50	0.309 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aS,13aS)-8-chloro-3-methyl-1- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.316 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(R)- or (S)-1-isopropyl-3,7-dimethyl-10- (trifluoromethyl)-1,5,6,7,8,14-hexahydro- 9,13-(azeno)pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.331 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
1’,3’-dimethyl-8’-(trifluoromethyl)- 1’,4’,10’,11’-tetrahydro-13’H- spiro[cyclopropane-1,12’- 5,9pyrazolo[3,4- b][1]oxa[4,6,10]triazacyclotridecine]	IC50	0.339 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aR,12aR)-8-chloro-3-methyl-1- (trifluoromethyl)-3,4,10,10a,11,12,12a,13- octahydro-5,9- (azeno)cyclobuta[k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.339 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
US20250313575, Ex-5.2	IC50	0.347 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
ethyl 2-((10aS,13aS)-3-cyclopropyl-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecin-1- yl)acetate	IC50	0.355 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aS,13aS)-8-chloro-1-ethyl-3- (trifluoromethyl)-1,4,10a,11,13a,14- hexahydro-10H,13H-5,9- (azeno)furo[3,4-k]pyrazolo[3,4- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.38 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aR,12aR)-8-chloro-3-cyclopropyl-1- methyl-3,4,10,10a,11,12,12a,13-octahydro- 5,9-(azeno)cyclobuta[k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.389 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
US20250313575, Ex-20.2	IC50	0.407 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
(10aS,13aS)-3-cyclobutyl-1-((1S,2S)- or (10aS,13aS)-3-cyclobutyl-1-((IR,2R)-2-(1- methyl-1H-pyrazol-4-yl)cyclopropyl)-8- (trifluoromethyl)-3,4,10a,11,13a,14- hexahydro-10H,13H-5,9-(azeno)furo[3,4- k]pyrazolo[4,3- b][1]oxa[4,6,10]triazacyclotridecine	IC50	0.447 nM	US-20250313575: MACROCYCLES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
3-[6-[4-(2-fluoroethyl)piperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropyl)oxy-2,3,3a,4,5,6,7,7a-octahydro-1H-indazole	IC50	0.45 nM	US-9493440: Compounds inhibiting leucine-rich repeat kinase enzyme activity
5-(1-methylcyclopropyl)oxy-3-[6-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]pyrimidin-4-yl]-2,3,3a,4,5,6,7,7a-octahydro-1H-indazole	IC50	0.49 nM	US-9493440: Compounds inhibiting leucine-rich repeat kinase enzyme activity
2-N-[3-chloro-1-[2-(1-methyl-1,2,4-triazol-3-yl)propan-2-yl]pyrazol-4-yl]-4-N-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.5 nM	US-9212173: Pyrazole aminopyrimidine derivatives as LRRK2 modulators
7-[4-(dimethylcarbamoyl)phenyl]cinnoline-3-carboxamide	IC50	0.5 nM	US-9884828: Substituted cinnolines as inhibitors of LRRK2 kinase activity
3-methoxy-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-(1-methylpiperidin-4-yl)benzamide	KI	0.6 nM	US-8802674: Aminopyrimidine derivatives as LRRK2 modulators
[4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fluoro-5-methoxyphenyl]-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methanone	KI	0.6 nM	US-8802674: Aminopyrimidine derivatives as LRRK2 modulators
4-N-ethyl-2-N-[3-methyl-1-[2-(1-propan-2-yl-1,2,4-triazol-3-yl)propan-2-yl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.6 nM	US-9212173: Pyrazole aminopyrimidine derivatives as LRRK2 modulators
2-N-[1-[(3S)-3-fluorooxan-4-yl]-3-methylpyrazol-4-yl]-4-N-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.6 nM	US-9212173: Pyrazole aminopyrimidine derivatives as LRRK2 modulators
2-N-[1-[(3R)-3-fluorooxan-4-yl]-5-methylpyrazol-4-yl]-4-N-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.6 nM	US-9212173: Pyrazole aminopyrimidine derivatives as LRRK2 modulators
2-N-(5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-3-yl)-4-N-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine	KI	0.6 nM	US-9212186: Bicyclic pyrazole LRRK2 small molecule inhibitors
BDBM257389	IC50	0.6 nM	US-9493440: Compounds inhibiting leucine-rich repeat kinase enzyme activity
BDBM257386	IC50	0.6 nM	US-9493440: Compounds inhibiting leucine-rich repeat kinase enzyme activity
2-[[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropyl)oxy-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]methyl]-1,3-oxazole	IC50	0.6 nM	US-9493440: Compounds inhibiting leucine-rich repeat kinase enzyme activity
3-[6-[(3S)-4-(1-methoxypropan-2-yl)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropyl)oxy-2,3,3a,4,5,6,7,7a-octahydro-1H-indazole	IC50	0.6 nM	US-9493440: Compounds inhibiting leucine-rich repeat kinase enzyme activity
3-[6-[(3S)-4-ethyl-3-methylpiperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropyl)oxy-2,3,3a,4,5,6,7,7a-octahydro-1H-indazole	IC50	0.6 nM	US-9493440: Compounds inhibiting leucine-rich repeat kinase enzyme activity

ChEMBL bioactivities

5594 potent at pChembl≥5 of 5689 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	Ki	0.06	nM	CHEMBL3969077
10.19	IC50	0.06457	nM	CHEMBL5189225
10.12	IC50	0.07586	nM	CHEMBL5195441
10.09	IC50	0.08128	nM	CHEMBL5198416
10.09	IC50	0.08128	nM	CHEMBL5177202
10.09	IC50	0.08128	nM	CHEMBL5191262
10.09	IC50	0.08128	nM	CHEMBL5171075
10.09	IC50	0.08128	nM	CHEMBL5283649
10.09	IC50	0.08128	nM	CHEMBL5273196
10.09	IC50	0.08128	nM	CHEMBL5266868
10.09	IC50	0.08128	nM	CHEMBL5276281
10.09	IC50	0.08128	nM	CHEMBL5283143
10.09	IC50	0.08128	nM	CHEMBL5289583
10.08	IC50	0.08318	nM	CHEMBL5200393
10.00	Ki	0.1	nM	CHEMBL3969077
10.00	Ki	0.1	nM	CHEMBL5075978
10.00	IC50	0.1	nM	CHEMBL5203973
9.96	IC50	0.11	nM	CHEMBL5422978
9.77	IC50	0.169	nM	CHEMBL5206036
9.76	IC50	0.1742	nM	CHEMBL5199715
9.73	IC50	0.1875	nM	CHEMBL5201483
9.70	Ki	0.2	nM	CHEMBL5091909
9.70	IC50	0.2	nM	CHEMBL5396547
9.70	IC50	0.2	nM	CHEMBL5575868
9.70	IC50	0.2	nM	CHEMBL5593518
9.52	Ki	0.3	nM	CHEMBL2152707
9.52	Ki	0.3	nM	CHEMBL3942517
9.52	Ki	0.3	nM	CHEMBL3923102
9.52	Ki	0.3	nM	CHEMBL3890082
9.52	Ki	0.3	nM	CHEMBL5075978
9.52	IC50	0.3	nM	CHEMBL5172416
9.52	IC50	0.3	nM	CHEMBL5267350
9.52	IC50	0.3	nM	CHEMBL5286106
9.52	IC50	0.3	nM	CHEMBL5270706
9.52	IC50	0.3	nM	CHEMBL5593518
9.50	Ki	0.3162	nM	CHEMBL1993661
9.41	Kd	0.39	nM	STAUROSPORINE
9.40	Ki	0.4	nM	CHEMBL5091909
9.40	Ki	0.4	nM	CHEMBL5086513
9.40	IC50	0.4	nM	CHEMBL5181104
9.40	IC50	0.4	nM	MLi-2
9.40	IC50	0.4	nM	CHEMBL5284341
9.40	IC50	0.4	nM	CHEMBL5274608
9.40	IC50	0.4	nM	CHEMBL5436466
9.40	IC50	0.4	nM	CHEMBL5408287
9.40	Ki	0.3981	nM	CHEMBL1980995
9.36	IC50	0.44	nM	CHEMBL5279036
9.35	IC50	0.4508	nM	CHEMBL5204653
9.35	IC50	0.45	nM	CHEMBL6054778
9.31	IC50	0.49	nM	CHEMBL5884560

PubChem BioAssay actives

2216 with measured affinity, of 3352 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[[5-chloro-4-(4-hydroxy-4-methylcyclohexyl)oxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-N,N-dimethyl-3-[(2R)-1,1,1-trifluoropropan-2-yl]oxybenzamide	1551592: Inhibition of recombinant human GST-tagged LRRK2 G2019S mutant catalytic domain (970 to 2527 residues) expressed in baculovirus expression system using LRRKtide as substrate measured after 1 hr by Alexa-fluor-647 ADP tracer-based ADAPTA assay	ic50	<0.0001	uM
4-amino-7-methyl-2-[(1-methylpyrazol-4-yl)amino]-6-[(2R)-2-methylpyrrolidin-1-yl]pyrrolo[2,3-d]pyrimidine-5-carbonitrile	1817497: Binding affinity to human LRRK2 WT incubated for 2 hrs by TR-FRET based Lanthascreen kinase activity assay	ki	0.0001	uM
1-[4-[6-chloro-2-[(5-chloro-1-cyclopropylpyrazol-4-yl)amino]quinazolin-7-yl]piperazin-1-yl]-2-methylpropan-2-ol	1880266: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate preincubated for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP at Km concentration by TR-FRET Lanthascreen assay	ic50	0.0001	uM
N-[7-chloro-6-(4-cyanopiperidin-1-yl)isoquinolin-3-yl]-2-pyrimidin-5-ylcyclopropane-1-carboxamide	1870713: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of ATP by TR-FRET based LanthaScreen assay	ic50	0.0001	uM
2-ethyl-N-[6-[4-(4-fluoro-3-methyloxolan-3-yl)piperazin-1-yl]-7-methylisoquinolin-3-yl]-3-(1-methylpyrazol-4-yl)cyclopropane-1-carboxamide	1870713: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of ATP by TR-FRET based LanthaScreen assay	ic50	0.0001	uM
trans-(1R,2R)-N-[7-chloro-6-[1-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperidin-4-yl]isoquinolin-3-yl]-2-(2-methoxypropan-2-yl)cyclopropane-1-carboxamide	2020461: Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 residues) (unknown origin) using LRRKtide peptide as substrate assessed as inhibition of substrate phosphorylation preincubated with compound for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
N-[7-chloro-6-[4-(4-hydroxy-3-methyloxolan-3-yl)piperazin-1-yl]isoquinolin-3-yl]-2-methyl-2-(oxolan-3-yl)cyclopropane-1-carboxamide	1870713: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of ATP by TR-FRET based LanthaScreen assay	ic50	0.0001	uM
N-[7-chloro-6-[4-(4-hydroxy-3-methyloxolan-3-yl)piperazin-1-yl]isoquinolin-3-yl]-2-(2-methyltriazol-4-yl)cyclopropane-1-carboxamide	1870713: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of ATP by TR-FRET based LanthaScreen assay	ic50	0.0001	uM
N-[7-chloro-6-[4-(4-hydroxy-3-methyloxolan-3-yl)piperazin-1-yl]isoquinolin-3-yl]-2-thiophen-2-ylcyclopropane-1-carboxamide	1870713: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of ATP by TR-FRET based LanthaScreen assay	ic50	0.0001	uM
2-[2-[[5-chloro-1-(oxan-4-yl)pyrazol-4-yl]amino]quinazolin-7-yl]spiro[2.2]pentane-2-carbonitrile	1821426: Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 residues) (unknown origin) preincubated with enzyme for 15 mins followed by fluorescein-labeled LRRKtide peptide substrate and ATP addition for 90 mins by TR-FRET assay	ic50	0.0001	uM
5-chloro-N-[7-chloro-6-[1-(4-hydroxy-3-methyloxolan-3-yl)piperidin-4-yl]isoquinolin-3-yl]-1-cyclopropylpyrazole-4-carboxamide	1948821: Inhibition of GST20-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate by Lantha screen assay	ic50	0.0001	uM
1-[6-chloro-2-[(5-methyl-4,5-dihydro-1H-pyrazol-4-yl)amino]quinazolin-7-yl]-3,4-dimethylpiperidin-4-ol	1880266: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate preincubated for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP at Km concentration by TR-FRET Lanthascreen assay	ic50	0.0001	uM
N-[7-chloro-6-[4-(4-hydroxy-3-methyloxolan-3-yl)piperazin-1-yl]isoquinolin-3-yl]-2-ethoxycyclopropane-1-carboxamide	1870713: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition measured after 90 mins in presence of ATP by TR-FRET based LanthaScreen assay	ic50	0.0001	uM
N-[7-chloro-6-[1-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperidin-4-yl]isoquinolin-3-yl]cyclopropanecarboxamide	2020461: Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 residues) (unknown origin) using LRRKtide peptide as substrate assessed as inhibition of substrate phosphorylation preincubated with compound for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
N-[7-chloro-6-[1-(4-hydroxy-3-methyloxolan-3-yl)piperidin-4-yl]isoquinolin-3-yl]-2-pyridin-4-ylacetamide	1948821: Inhibition of GST20-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate by Lantha screen assay	ic50	0.0001	uM
N-[7-chloro-6-[(3S,4S)-3-fluoro-1-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperidin-4-yl]isoquinolin-3-yl]spiro[2.2]pentane-2-carboxamide	1948821: Inhibition of GST20-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate by Lantha screen assay	ic50	0.0001	uM
N-[7-fluoro-6-[1-(4-hydroxy-3-methyloxolan-3-yl)piperidin-4-yl]isoquinolin-3-yl]-2-pyridin-2-ylcyclopropane-1-carboxamide	1948821: Inhibition of GST20-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate by Lantha screen assay	ic50	0.0001	uM
N-[6-[1-(4-hydroxy-3-methyloxolan-3-yl)piperidin-4-yl]-7-methylisoquinolin-3-yl]-6-oxaspiro[2.5]octane-2-carboxamide	1948821: Inhibition of GST20-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate by Lantha screen assay	ic50	0.0001	uM
N-[7-chloro-6-[1-(4-hydroxy-3-methyloxolan-3-yl)piperidin-4-yl]isoquinolin-3-yl]-2-(2-methyltriazol-4-yl)cyclopropane-1-carboxamide	1948821: Inhibition of GST20-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate by Lantha screen assay	ic50	0.0001	uM
N-[6-[1-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperidin-4-yl]-7-methylisoquinolin-3-yl]spiro[2.2]pentane-2-carboxamide	2020461: Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 residues) (unknown origin) using LRRKtide peptide as substrate assessed as inhibition of substrate phosphorylation preincubated with compound for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
cis-(1R,2S)-N-[7-chloro-6-[1-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperidin-4-yl]isoquinolin-3-yl]-2-(2-hydroxypropan-2-yl)cyclopropane-1-carboxamide	2020461: Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 residues) (unknown origin) using LRRKtide peptide as substrate assessed as inhibition of substrate phosphorylation preincubated with compound for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP by TR-FRET assay	ic50	0.0001	uM
4-(3-methylphenyl)-6-[(1-methylpyrazol-3-yl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile	1476637: Inhibition of wild type recombinant human GST-tagged LRRK2 (970 to 2527 residues) expressed in baculovirus using fluorescein-LRRKtide as substrate after 2 hrs by TR-FRET assay	ki	0.0001	uM
[3-(difluoromethoxy)-4-[(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]phenyl]-(4-methylpiperazin-1-yl)methanone	1715859: Inhibition of recombinant His6-Tev-LRRK2 (1326 to 2527 residues) (unknown origin) using LRRKtide as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs in presence of ATP by TR-FRET assay	ic50	0.0002	uM
4,5-dimethyl-N-[3-(4-sulfamoylphenyl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943170: Inhibition of N-terminal GST-fused human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
(7S)-4,5,7-trimethyl-N-[3-(2-morpholin-4-yl-4-pyridinyl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943170: Inhibition of N-terminal GST-fused human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
(7R)-4,5,7-trimethyl-N-[3-(2-morpholin-4-yl-4-pyridinyl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943169: Inhibition of N-terminal GST-fused human wild type LRRK2 using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
4,5-dimethyl-N-[3-(2-morpholin-4-yl-4-pyridinyl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943169: Inhibition of N-terminal GST-fused human wild type LRRK2 using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
N-[3-(1H-benzimidazol-2-yl)-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943170: Inhibition of N-terminal GST-fused human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
4,5,7,7-tetramethyl-N-(3-phenyl-1H-indazol-5-yl)tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943170: Inhibition of N-terminal GST-fused human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
(5S)-5-[[3-(1,3-oxazol-5-yl)-1H-indazol-5-yl]oxy]-5,6,7,8-tetrahydronaphthalene-2-carbonitrile	2015350: Inhibition of LRRK2 G2019S mutant (unknown origin) using LRRKtide as substrate pre-incubated for 15 min and measured after 1 hrs by HTRF assay	ic50	0.0002	uM
(7R)-4,5,7-trimethyl-N-(3-pyridin-4-yl-1H-indazol-5-yl)-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943169: Inhibition of N-terminal GST-fused human wild type LRRK2 using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
4,5,7,7-tetramethyl-N-[3-(2-morpholin-4-yl-4-pyridinyl)-1H-indazol-5-yl]tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943170: Inhibition of N-terminal GST-fused human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0002	uM
1-[6-chloro-2-[(5-chloro-1-cyclopropylpyrazol-4-yl)amino]quinazolin-7-yl]-3-methylpyrrolidin-3-ol	1880266: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate preincubated for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP at Km concentration by TR-FRET Lanthascreen assay	ic50	0.0002	uM
N-[1-(1-bicyclo[1.1.1]pentanyl)-5-chloropyrazol-4-yl]-6-chloro-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)quinazolin-2-amine	1880266: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate preincubated for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP at Km concentration by TR-FRET Lanthascreen assay	ic50	0.0002	uM
4-amino-7-methyl-6-[(2R)-2-methylpyrrolidin-1-yl]-2-(1H-pyrazol-4-ylamino)pyrrolo[2,3-d]pyrimidine-5-carbonitrile	1817497: Binding affinity to human LRRK2 WT incubated for 2 hrs by TR-FRET based Lanthascreen kinase activity assay	ki	0.0002	uM
6-chloro-N-[1-(2,2-dimethylpropyl)pyrazol-4-yl]-7-[4-(3-methyloxetan-3-yl)piperidin-1-yl]quinazolin-2-amine	1880266: Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein labeled LRRKtide peptide as substrate preincubated for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP at Km concentration by TR-FRET Lanthascreen assay	ic50	0.0002	uM
17-methoxy-12-methyl-6-(trifluoromethyl)-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(17),3,5,7(19),14(18),15-hexaen-13-one	2106407: Inhibition of human LRRK2 G2019S mutant using [RLGRDKYKTLRQIRQ] peptide substrate by [Gamma33P]-ATP assay	ic50	0.0002	uM
(2S)-N-[7-chloro-6-[1-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperidin-4-yl]isoquinolin-3-yl]-6-oxaspiro[2.5]octane-2-carboxamide	2020461: Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 residues) (unknown origin) using LRRKtide peptide as substrate assessed as inhibition of substrate phosphorylation preincubated with compound for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP by TR-FRET assay	ic50	0.0002	uM
17-methoxy-8,12-dimethyl-6-(trifluoromethyl)-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(17),3,5,7(19),14(18),15-hexaen-13-one	2106407: Inhibition of human LRRK2 G2019S mutant using [RLGRDKYKTLRQIRQ] peptide substrate by [Gamma33P]-ATP assay	ic50	0.0002	uM
(2S)-2-[1-[6-[4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-yl]indazol-6-yl]spiro[2.2]pentane-2-carbonitrile	1936251: Inhibition of GST20-tagged LRRK2 in human SH-SY5Y cells assessed as reduction in pSer935 phosphorylation incubated for 90 mins by MSD assay	ic50	0.0003	uM
N-[5-[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]-2-(trifluoromethyl)-3-pyridinyl]-6-[1-[[1-(trifluoromethyl)cyclopropyl]methyl]pyrazol-4-yl]pyridine-2-carboxamide	1853258: Inhibition of human LRRK2 G2019S mutant expressed in human SH-SY5Y cells assessed as inhibition of tetracycline induced LRRK2 phosphorylation at Ser935 residue incubated for 90 mins by MSD assay	ic50	0.0003	uM
4-cyclohexyloxy-3-[(E)-2-(1-methylpyrazol-4-yl)ethenyl]-2H-pyrazolo[4,3-c]pyridine	692847: Binding affinity to LRRK2	ki	0.0003	uM
(2R,6S)-2,6-dimethyl-4-[4-[5-(1-methylpyrazol-4-yl)-1H-indazol-3-yl]-2-pyridinyl]morpholine	1936250: Inhibition of GST20-tagged human LRRK2 G2019S mutant using LRRKtide peptide preincubated for 15 mins followed by substrate addition and measured after 90 mins by TR-FRET assay	ic50	0.0003	uM
4,5-dimethyl-N-(3-pyridin-4-yl-1H-indazol-5-yl)-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943170: Inhibition of N-terminal GST-fused human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0004	uM
4,5-dimethyl-N-[3-(6-morpholin-4-ylpyrimidin-4-yl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide	1943170: Inhibition of N-terminal GST-fused human LRRK2 G2019S mutant using fluorescein-labeled LRRKtide as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0004	uM
4-amino-7-methyl-6-[(2R)-2-methylpyrrolidin-1-yl]pyrrolo[2,3-d]pyrimidine-5-carbonitrile	1817497: Binding affinity to human LRRK2 WT incubated for 2 hrs by TR-FRET based Lanthascreen kinase activity assay	ki	0.0004	uM
(2S)-N-[7-chloro-6-[4-[(3R,4R)-4-hydroxy-3-methyloxolan-3-yl]piperazin-1-yl]isoquinolin-3-yl]-6-oxaspiro[2.5]octane-2-carboxamide	2020461: Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 residues) (unknown origin) using LRRKtide peptide as substrate assessed as inhibition of substrate phosphorylation preincubated with compound for 15 mins followed by substrate addition and measured after 90 mins in presence of ATP by TR-FRET assay	ic50	0.0004	uM
6-[1-(cyclopropylmethyl)pyrazol-4-yl]-N-[5-[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]-2-(trifluoromethyl)-3-pyridinyl]pyridine-2-carboxamide	1853258: Inhibition of human LRRK2 G2019S mutant expressed in human SH-SY5Y cells assessed as inhibition of tetracycline induced LRRK2 phosphorylation at Ser935 residue incubated for 90 mins by MSD assay	ic50	0.0004	uM
(1S)-1-[[3-(1,3-oxazol-5-yl)-1H-indazol-5-yl]oxy]-2,3-dihydro-1H-indene-5-carbonitrile	2015350: Inhibition of LRRK2 G2019S mutant (unknown origin) using LRRKtide as substrate pre-incubated for 15 min and measured after 1 hrs by HTRF assay	ic50	0.0004	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624741: Binding constant for LRRK2(G2019S) kinase domain	kd	0.0004	uM

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Rotenone	increases response to substance, decreases response to substance, affects reaction, decreases reaction	4
1-Methyl-4-phenylpyridinium	affects reaction, increases activity, increases reaction, increases expression, decreases reaction (+1 more)	4
Paraquat	affects cotreatment, decreases reaction, increases phosphorylation, decreases response to substance	3
Valproic Acid	increases expression, decreases methylation, affects cotreatment	3
Cadmium	increases abundance, increases expression, decreases expression	2
Manganese	increases expression, increases response to substance, affects cotreatment, decreases reaction	2
Plant Extracts	affects cotreatment, increases expression, decreases reaction, increases phosphorylation	2
3-(4-(morpholin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl)benzonitrile	affects cotreatment, decreases reaction, increases phosphorylation, decreases activity	1
abivertinib	decreases activity	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases methylation	1
titanium dioxide	increases methylation	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	decreases reaction, increases reaction, decreases phosphorylation, increases ubiquitination, affects binding	1
butyraldehyde	decreases expression	1
3-methyladenine	decreases reaction, increases response to substance	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
bafilomycin A1	increases response to substance	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
mithramycin A	decreases reaction, increases expression, decreases expression	1
lactacystin	increases ubiquitination	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases ubiquitination	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1

ChEMBL screening assays

809 unique, capped per target: 799 binding, 7 admet, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1073732	Binding	Inhibition of LRRK2 at 3 to 6 uM relative to control	Hit to lead account of the discovery of bisbenzamide and related ureidobenzamide inhibitors of Rho kinase. — J Med Chem
CHEMBL1963806	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: LRRK2	PubChem BioAssay data set
CHEMBL4018177	ADMET	Inhibition of full length wild-type LRRK2 (unknown origin) using biotinylated ezrin/radaxin/meosin peptide as substrate measured after 1 hr	Discovery of LRRK2 inhibitors by using an ensemble of virtual screening methods. — Bioorg Med Chem Lett

Cellosaurus cell lines

279 cell lines: 214 induced pluripotent stem cell, 35 finite cell line, 14 transformed cell line, 9 cancer cell line, 7 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_9S14	IB PD-G1	Induced pluripotent stem cell	Female
CVCL_9S15	IB PD-G2	Induced pluripotent stem cell	Male
CVCL_A1YC	KEIUi001-A	Induced pluripotent stem cell	Female
CVCL_A1YD	LB16	Induced pluripotent stem cell	Female
CVCL_A1YE	LB21	Induced pluripotent stem cell	Female
CVCL_A3BX	SHEHDNi002-A	Induced pluripotent stem cell	Female
CVCL_A4MN	iPD-T1	Induced pluripotent stem cell	Male
CVCL_A4MP	iPD-T2	Induced pluripotent stem cell	Male
CVCL_A4MQ	iPD-C1	Induced pluripotent stem cell	Male
CVCL_A4MR	iPD-C2	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients
NCT00642356	PHASE4	TERMINATED	Carbidopa/Levodopa/Entacapone Versus Immediate Release (IR) Carbidopa/Levodopa on Non-motor Symptoms in Patients With Idiopathic Parkinson’s Disease and Demonstrating Non-motor Symptoms of Wearing Off
NCT00646204	PHASE4	COMPLETED	Namenda (Memantine) for Non-motor Symptoms in Parkinson’s Disease