AAK1

Summary

AAK1 (AP2 associated kinase 1, HGNC:19679) is a protein-coding gene on chromosome 2p13.3, encoding AP2-associated protein kinase 1 (Q2M2I8). Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis.

This gene encodes a member of the SNF1 subfamily of serine/threonine protein kinases. Adaptor-related protein complex 2 (AP-2 complexes) functions during receptor-mediated endocytosis to trigger clathrin assembly, interact with membrane-bound receptors, and recruit encodytic accessory factors. The encoded protein interacts with and phosphorylates a subunit of the AP-2 complex, which promotes binding of AP-2 to sorting signals found in membrane-bound receptors and subsequent receptor endocytosis. Its kinase activity is stimulated by clathrin. This kinase has been shown to play an important role in regulating the clathrin-mediated endocytosis of the rabies virus, facilitating infection. Inhibitors of this kinase are being studied as candidate therapeutics to disrupt the entry of viruses, including SARS-CoV-2, into target cells. It is also involved in positive regulation of Notch pathway signaling in mammals. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

Source: NCBI Gene 22848 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 153 total — 2 pathogenic, 2 likely-pathogenic
• Druggable target: yes — 59 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014911

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19679
Approved symbol	AAK1
Name	AP2 associated kinase 1
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1048, DKFZp686K16132
Ensembl gene	ENSG00000115977
Ensembl biotype	protein_coding
OMIM	616405
Entrez	22848

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000406297, ENST00000409068, ENST00000409085, ENST00000461002, ENST00000470281, ENST00000471775, ENST00000489327, ENST00000492192, ENST00000495239, ENST00000495836, ENST00000606389, ENST00000623317, ENST00000624900, ENST00000892833

RefSeq mRNA: 5 — MANE Select: NM_014911 NM_001371575, NM_001371577, NM_001426745, NM_001426746, NM_014911

CCDS: CCDS1893

Canonical transcript exons

ENST00000409085 — 22 exons

Exon	Start	End
ENSE00000759074	69514471	69514749
ENSE00000759174	69520834	69520988
ENSE00000759183	69525033	69525112
ENSE00000759214	69527216	69527319
ENSE00000759240	69530008	69530140
ENSE00000759264	69530625	69530706
ENSE00000759279	69532041	69532162
ENSE00001006476	69544436	69544544
ENSE00001239161	69509231	69509460
ENSE00001239208	69518954	69519240
ENSE00001580157	69478951	69479061
ENSE00001585397	69476880	69476990
ENSE00001948703	69457997	69475963
ENSE00003520238	69505569	69505673
ENSE00003526179	69495985	69496080
ENSE00003543075	69482711	69482812
ENSE00003561315	69507421	69507578
ENSE00003562640	69542523	69542665
ENSE00003565262	69556860	69556978
ENSE00003569520	69480860	69480961
ENSE00003668079	69642878	69643274
ENSE00003841879	69643575	69643739

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.6030 / max 2138.6885, expressed in 1770 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28931	7.9589	1678
28934	4.8699	1532
28933	0.9669	526
28932	0.7998	459
28929	0.7591	204
28936	0.5542	219
28935	0.2753	121
28928	0.1569	66
28912	0.1278	56
28927	0.0542	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.81	gold quality
renal medulla	UBERON:0000362	97.86	gold quality
pons	UBERON:0000988	97.57	gold quality
superior vestibular nucleus	UBERON:0007227	97.17	gold quality
ventral tegmental area	UBERON:0002691	97.06	gold quality
cardia of stomach	UBERON:0001162	97.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.92	gold quality
pylorus	UBERON:0001166	96.88	gold quality
medulla oblongata	UBERON:0001896	96.78	gold quality
inferior vagus X ganglion	UBERON:0005363	96.69	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.47	gold quality
parietal lobe	UBERON:0001872	96.38	gold quality
dorsal root ganglion	UBERON:0000044	96.20	gold quality
trigeminal ganglion	UBERON:0001675	96.11	gold quality
postcentral gyrus	UBERON:0002581	95.94	gold quality
lateral globus pallidus	UBERON:0002476	95.67	gold quality
nipple	UBERON:0002030	95.64	gold quality
subthalamic nucleus	UBERON:0001906	95.60	gold quality
saphenous vein	UBERON:0007318	95.42	gold quality
trachea	UBERON:0003126	95.34	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	95.33	gold quality
inferior olivary complex	UBERON:0002127	95.26	gold quality
corpus epididymis	UBERON:0004359	95.23	gold quality
CA1 field of hippocampus	UBERON:0003881	95.15	gold quality
substantia nigra pars compacta	UBERON:0001965	95.12	gold quality
seminal vesicle	UBERON:0000998	94.96	gold quality
superior frontal gyrus	UBERON:0002661	94.92	gold quality
middle temporal gyrus	UBERON:0002771	94.64	gold quality
entorhinal cortex	UBERON:0002728	94.58	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.56	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	25.26
E-ANND-3	yes	10.60
E-GEOD-137537	yes	5.68
E-MTAB-9067	yes	4.79
E-CURD-97	no	537.43
E-ENAD-17	no	282.37
E-CURD-112	no	3.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

951 targeting AAK1, 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-8485	100.00	77.57	4731
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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4673	100.00	66.64	1490

Literature-anchored findings (GeneRIF, showing 8)

• These observations suggest that AAK1 functions at multiple steps of the endosomal pathway by regulating transferrin internalization and its rapid recycling back to the plasma membrane from early/sorting endosome. (PMID:17494869)
• AAK1 increases the localization of activated Notch to Rab5-positive endocytic vesicles, while AAK1 depletion or overexpression of Numb, an inhibitor of the pathway, interferes with this localization. (PMID:21464124)
• AAK1 and GAK are critical regulators of HCV entry that function in part by activating EGFR, AP2M1, and NUMB, and as the molecular targets underlying the antiviral effect of sunitinib and erlotinib, respectively. (PMID:25653444)
• Two of these kinases that were classified as resistors were PX domain-containing serine/threonine kinase (PXK) and AP2-associated kinase 1 (AAK1), which promote receptor endocytosis and may enable cells to resist TRAIL-induced apoptosis (PMID:25852190)
• Results present the first structures of AAK1 and BIKE which reveal that all members of the Numb-associated kinase family share unusual activation segment architecture. (PMID:26853940)
• Author show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. (PMID:30605688)
• The Serine/Threonine Kinase AP2-Associated Kinase 1 Plays an Important Role in Rabies Virus Entry. (PMID:31905947)
• Extracellular vesicle-transmitted miR-671-5p alleviates lung inflammation and injury by regulating the AAK1/NF-kappaB axis. (PMID:36733250)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aak1a	ENSDARG00000011855
danio_rerio	aak1b	ENSDARG00000077686
mus_musculus	Aak1	ENSMUSG00000057230
rattus_norvegicus	Aak1	ENSRNOG00000018317

Paralogs (2): STK16 (ENSG00000115661), BMP2K (ENSG00000138756)

Protein

Protein identifiers

AP2-associated protein kinase 1 — Q2M2I8 (reviewed: Q2M2I8)

Alternative names: Adaptor-associated kinase 1

All UniProt accessions (5): Q2M2I8, A0A096LNZ0, A0A096LP25, A0A096LP60, E9PG46

UniProt curated annotations — full annotation on UniProt →

Function. Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Preferentially, may phosphorylate substrates on threonine residues. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity. (Microbial infection) By regulating clathrin-mediated endocytosis, AAK1 plays a role in the entry of hepatitis C virus as well as for the lifecycle of other viruses such as Ebola and Dengue.

Subunit / interactions. Interacts (via CBD domain) with clathrin. Interacts with AP-2 complex. Interacts with NUMB. Interacts with alpha-adaptin. Interacts with EPS15 isoform 2. Interacts with membrane-bound activated NOTCH1 but not with the inactive full-length form of NOTCH1. Preferentially interacts with monoubiquitinated activated NOTCH1 compared to the non-ubiquitinated form.

Subcellular location. Cell membrane. Membrane. Clathrin-coated pit. Presynapse.

Tissue specificity. Detected in brain, heart and liver. Isoform 1 is the predominant isoform in brain.

Post-translational modifications. Autophosphorylated.

Activity regulation. Stimulated by clathrin.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q2M2I8-1	1, AAK1L	yes
Q2M2I8-2	2, AAK1S

RefSeq proteins (5): NP_001358504, NP_001358506, NP_001413674, NP_001413675, NP_055726* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR051744	AP2_assoc_SerThr_kinase	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

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

UniProt features (83 total): modified residue 21, helix 14, compositionally biased region 11, strand 9, sequence variant 8, region of interest 7, turn 4, mutagenesis site 3, binding site 2, chain 1, domain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9F6S	X-RAY DIFFRACTION	1
9F8T	X-RAY DIFFRACTION	1.71
5TE0	X-RAY DIFFRACTION	1.9
4WSQ	X-RAY DIFFRACTION	1.95
5L4Q	X-RAY DIFFRACTION	1.97
9QB5	X-RAY DIFFRACTION	2
8GMD	X-RAY DIFFRACTION	2.2
8GMC	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2M2I8-F1	59.43	0.32

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): 176 (proton acceptor)

Ligand- & substrate-binding residues (2): 52–60; 74

Post-translational modifications (21): 1, 14, 234, 235, 354, 389, 391, 441, 606, 618, 620, 623, 624, 637, 650, 653, 687, 731, 846, 937 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
74	inhibits autophosphorylation and phosphorylation of ap2m1. does not affect numb localization. does not interact with mon
176	inhibits autophosphorylation and phosphorylation of ap2m1. does not affect numb localization.
777–779	does not affect interaction with notch1 but abolishes interaction with esp15.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 0 (showing top):

GO Biological Process (8): protein phosphorylation (GO:0006468), regulation of protein localization (GO:0032880), positive regulation of Notch signaling pathway (GO:0045747), protein stabilization (GO:0050821), membrane organization (GO:0061024), presynaptic endocytosis (GO:0140238), regulation of clathrin-dependent endocytosis (GO:2000369), endocytosis (GO:0006897)

GO Molecular Function (10): protein serine/threonine kinase activity (GO:0004674), Notch binding (GO:0005112), ATP binding (GO:0005524), AP-2 adaptor complex binding (GO:0035612), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (10): cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), clathrin-coated vesicle (GO:0030136), cell leading edge (GO:0031252), terminal bouton (GO:0043195), presynapse (GO:0098793), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
presynapse	2
protein kinase activity	2
membrane	2
phosphorylation	1
protein modification process	1
intracellular protein localization	1
regulation of localization	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
regulation of protein stability	1
cellular component organization	1
endocytosis	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
regulation of receptor-mediated endocytosis	1
clathrin-dependent endocytosis	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
signaling receptor binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein-containing complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
cell periphery	1
endomembrane system	1
coated vesicle	1
axon terminus	1
synapse	1

Protein interactions and networks

STRING

1246 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AAK1	ACE2	Q9BYF1	762
AAK1	AP2M1	P20172	732
AAK1	EPS15	P42566	679
AAK1	GAK	O14976	652
AAK1	SNAP91	O60641	610
AAK1	GABARAPL2	P60520	590
AAK1	AP2B1	P21851	586
AAK1	F5GZY7	F5GZY7	585
AAK1	JAK1	P23458	580
AAK1	AGTR2	P50052	556
AAK1	BIN1	O00499	526
AAK1	NUMB	P49757	517
AAK1	NUMBL	Q9Y6R0	514
AAK1	TMPRSS2	O15393	511
AAK1	JAK2	O60674	477

IntAct

91 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
RALBP1	JUN	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
AP2B1	AP2A2	psi-mi:“MI:0914”(association)	0.530
NECAP2	AP2A2	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
REPS1	AP2B1	psi-mi:“MI:0914”(association)	0.530
RALBP1	AP2B1	psi-mi:“MI:0914”(association)	0.530
REPS1	AAK1	psi-mi:“MI:0914”(association)	0.530
ATP13A2	AAK1	psi-mi:“MI:0915”(physical association)	0.510
AAK1	ATP13A2	psi-mi:“MI:0915”(physical association)	0.510
AP2M1	BCR/ABL fusion	psi-mi:“MI:0914”(association)	0.460
	TK2	psi-mi:“MI:0915”(physical association)	0.400
AAK1	AP2A1	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
E7	AP2A1	psi-mi:“MI:0914”(association)	0.350
E7	COPE	psi-mi:“MI:0914”(association)	0.350
	PLK4	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AHRR	psi-mi:“MI:0914”(association)	0.350

BioGRID (156): AP2A1 (Affinity Capture-MS), AP2B1 (Affinity Capture-MS), AP2M1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Proximity Label-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS), AAK1 (Affinity Capture-MS)

ESM2 similar proteins: A1Z9E2, A4QNP0, B0R0I6, B5DE69, F1MH24, F1SPM8, O08949, O94842, P0C1X8, P0CF24, P27699, P34333, P52655, P79145, Q01167, Q02086, Q03061, Q08CM4, Q09XV5, Q0IHV2, Q0P5K4, Q1LZH5, Q2M2I8, Q3TUF7, Q3UCQ1, Q3UHJ0, Q571G4, Q58NQ4, Q5E9U0, Q5QL03, Q5R6A9, Q5RBN8, Q5RCU0, Q641Z1, Q6DJL0, Q6IRR0, Q6MZP7, Q7ZUV7, Q7ZX03, Q86NP2

Diamond homologs: A2X6X1, A5A7I8, A8WRV1, F1MH24, F1SPM8, F4I4F2, G5ECQ3, O13839, O14976, O34507, O43066, O75716, O77676, O88697, P00516, P00517, P05130, P05132, P0C1X8, P0C605, P17157, P17612, P17948, P25321, P31374, P32023, P33981, P34100, P34331, P35761, P35916, P35917, P35969, P38070, P38080, P40494, P53767, P53974, P54119, P57760

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
AAK1	up-regulates	AP1M1	phosphorylation
AAK1	up-regulates	AP2M1	phosphorylation
AAK1	up-regulates	NUMB	phosphorylation
AAK1	unknown	NUMB	phosphorylation
STK38	“up-regulates activity”	AAK1	phosphorylation
“AP-2 complex”	“up-regulates activity”	AAK1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Activation of BAD and translocation to mitochondria	7	86.0×	1e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	75.8×	2e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	75.8×	2e-10
WNT5A-dependent internalization of FZD4	6	73.7×	4e-09
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	6	61.4×	1e-08
The role of Nef in HIV-1 replication and disease pathogenesis	6	61.4×	1e-08
VLDLR internalisation and degradation	5	57.6×	3e-07
Activation of BH3-only proteins	7	56.1×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
clathrin-dependent endocytosis	6	50.5×	5e-07
synaptic vesicle endocytosis	6	37.6×	2e-06
protein targeting	5	26.6×	1e-04
small GTPase-mediated signal transduction	6	15.9×	2e-04
intracellular protein localization	9	13.7×	3e-06
vesicle-mediated transport	7	9.8×	6e-04
intracellular protein transport	8	7.5×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	99
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1708190	GRCh37/hg19 2p25.1-q13(chr2:11504318-111365996)x1	Pathogenic
560065	Single allele	Pathogenic
152020	GRCh38/hg38 2p14-13.3(chr2:64587095-69876311)x1	Likely pathogenic
524189	Single allele	Likely pathogenic

SpliceAI

4299 predictions. Top by Δscore:

Variant	Effect	Δscore
2:69479101:T:C	acceptor_gain	1.0000
2:69479101:T:TC	acceptor_gain	1.0000
2:69480966:C:CT	acceptor_gain	1.0000
2:69480978:T:C	acceptor_gain	1.0000
2:69480978:T:TC	acceptor_gain	1.0000
2:69496111:C:CT	acceptor_gain	1.0000
2:69496112:A:T	acceptor_gain	1.0000
2:69507415:A:AC	donor_gain	1.0000
2:69507416:C:CC	donor_gain	1.0000
2:69507416:CTCA:C	donor_gain	1.0000
2:69507417:TCA:T	donor_loss	1.0000
2:69507418:CA:C	donor_loss	1.0000
2:69507419:A:AC	donor_gain	1.0000
2:69507419:ACCTT:A	donor_gain	1.0000
2:69507420:C:CC	donor_gain	1.0000
2:69507420:CCTT:C	donor_gain	1.0000
2:69507420:CCTTC:C	donor_gain	1.0000
2:69507592:C:T	acceptor_gain	1.0000
2:69507598:C:CT	acceptor_gain	1.0000
2:69507598:C:T	acceptor_gain	1.0000
2:69507614:A:C	acceptor_gain	1.0000
2:69509229:A:AC	donor_gain	1.0000
2:69509230:C:CC	donor_gain	1.0000
2:69509232:TGG:T	donor_gain	1.0000
2:69514469:A:AC	donor_gain	1.0000
2:69514470:C:CC	donor_gain	1.0000
2:69514470:CCG:C	donor_gain	1.0000
2:69520985:CAGT:C	acceptor_gain	1.0000
2:69520989:C:CC	acceptor_gain	1.0000
2:69525121:T:TC	acceptor_gain	1.0000

AlphaMissense

6277 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:69475882:A:G	L958P	1.000
2:69476909:A:G	I921T	1.000
2:69476909:A:T	I921N	1.000
2:69476917:A:C	F918L	1.000
2:69476917:A:T	F918L	1.000
2:69476919:A:G	F918L	1.000
2:69507450:A:G	L712P	1.000
2:69507453:A:G	L711P	1.000
2:69507468:A:G	L706P	1.000
2:69507502:A:G	W695R	1.000
2:69507502:A:T	W695R	1.000
2:69520937:C:A	R369S	1.000
2:69520937:C:G	R369S	1.000
2:69520938:C:A	R369M	1.000
2:69520938:C:G	R369T	1.000
2:69520945:G:T	R367S	1.000
2:69520953:A:T	I364N	1.000
2:69527288:C:A	R301S	1.000
2:69527288:C:G	R301S	1.000
2:69527310:A:G	L294S	1.000
2:69530084:A:C	S265R	1.000
2:69530084:A:T	S265R	1.000
2:69530086:T:G	S265R	1.000
2:69530092:C:A	G263W	1.000
2:69530093:A:C	F262L	1.000
2:69530093:A:T	F262L	1.000
2:69530095:A:G	F262L	1.000
2:69530105:G:C	F258L	1.000
2:69530105:G:T	F258L	1.000
2:69530107:A:G	F258L	1.000

dbSNP variants (sampled 300 via entrez): RS1000014394 (2:69470603 G>T), RS1000031983 (2:69572817 T>C), RS1000045646 (2:69467528 G>A,C), RS1000049146 (2:69517044 T>C), RS1000073201 (2:69520526 T>C), RS1000074272 (2:69644345 T>C), RS1000091257 (2:69473978 C>G), RS1000108202 (2:69472547 G>T), RS1000111415 (2:69572501 C>T), RS1000146317 (2:69560224 T>G), RS1000146745 (2:69603547 T>A,C), RS1000151193 (2:69621960 G>A), RS1000191981 (2:69512124 G>A), RS1000208534 (2:69638946 C>T), RS1000212803 (2:69485799 C>T)

Disease associations

OMIM: gene MIM:616405 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000490_5	Parkinson’s disease (age of onset)	9.000000e-06
GCST002120_5	Metabolite levels (Dihydroxy docosatrienoic acid)	6.000000e-06
GCST002707_11	Serum thyroid-stimulating hormone levels	6.000000e-06
GCST008295_5	Number of decayed, missing and filled tooth surfaces or use of dentures	7.000000e-10
GCST008306_32	Dentures	2.000000e-09
GCST008971_45	Urate levels	1.000000e-12
GCST008972_153	Urate levels	4.000000e-16
GCST90002383_183	Hematocrit	8.000000e-09
GCST90002384_227	Hemoglobin	1.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0005275	dihydroxy docosatrienoic acid measurement
EFO:0010078	dentures
EFO:0004531	urate measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3830 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

59 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 331,702 (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
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1614701	SELUMETINIB	4	10,221
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2105759	BARICITINIB	4	6,741
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301607	FILGOTINIB	4	2,905
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3622821	UPADACITINIB	4	2,726
CHEMBL3813873	PEXIDARTINIB	4	3,586
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL274654	ORANTINIB	3
CHEMBL300138	ENZASTAURIN	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3
CHEMBL1614713	CC-401	2
CHEMBL1667969	SAR-407899 FREE BASE	2
CHEMBL1721885	SU-014813	2
CHEMBL1822792	MK-2461	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — NAK family

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
forazapadin	Inhibition	9.0	pIC50
pilavapadin	Inhibition	8.7	pIC50
compound 21b [PMID: 31136173]	Inhibition	8.4	pIC50
BMS-911172	Inhibition	7.92	pIC50
baricitinib	Inhibition	7.77	pKd
compound 13 [PMID: 34333981]	Inhibition	7.13	pIC50
compound 6 [PMID: 34333981]	Inhibition	7.1	pIC50

Binding affinities (BindingDB)

579 measured of 579 human assays (579 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-1-(2-cyclopropyl-4-quinolin-4-ylphenoxy)-2,4-dimethylpentan-2-amine	IC50	0.07 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-4-(trifluoromethyl)-2-pyridinyl]-2-pyridinyl]carbamate	IC50	0.19 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[6-[(2S)-2-amino-2,4-dimethylpentoxy]-5-(difluoromethyl)-3-pyridinyl]-2-pyridinyl]carbamate	IC50	0.2 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[3-(difluoromethyl)-5-quinolin-4-yl-2-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.23 nM	US-10351563: Biaryl kinase inhibitors
(2S)-2,4-dimethyl-1-[[6-quinolin-4-yl-4-(trifluoromethyl)-3-pyridinyl]oxy]pentan-2-amine	IC50	0.24 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[3-(difluoromethyl)-5-(7-fluoroquinolin-4-yl)-2-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.25 nM	US-10351563: Biaryl kinase inhibitors
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-cyanophenyl]-2-pyridinyl]acetamide	IC50	0.3 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[4-(difluoromethyl)-6-quinolin-4-yl-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.3 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)-2-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.31 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-cyclopropylphenyl]-2-pyridinyl]carbamate	IC50	0.32 nM	US-10351563: Biaryl kinase inhibitors
(2S)-2,4-dimethyl-1-[4-(1,6-naphthyridin-4-yl)-2-(trifluoromethyl)phenoxy]pentan-2-amine	IC50	0.32 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(trifluoromethyl)phenyl]-2-pyridinyl]carbamate	IC50	0.34 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[4-(difluoromethyl)-6-(5-fluoro-2-methyl-4-pyridinyl)-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.34 nM	US-10351563: Biaryl kinase inhibitors
N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(trifluoromethyl)phenyl]-2-pyridinyl]acetamide	IC50	0.36 nM	US-10351563: Biaryl kinase inhibitors
BDBM406253	IC50	0.36 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[2-(difluoromethyl)-4-(2-methyl-4-pyridinyl)phenoxy]-2,4-dimethylpentan-2-amine	IC50	0.38 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[6-[(2S)-2-amino-2,4-dimethylpentoxy]-5-(trifluoromethyl)-3-pyridinyl]-2-pyridinyl]carbamate	IC50	0.38 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[4-chloro-6-(6-chloroquinolin-4-yl)-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.39 nM	US-10351563: Biaryl kinase inhibitors
tert-butyl N-[(2S)-1-[2-cyano-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenoxy]-2,4-dimethylpentan-2-yl]carbamate	IC50	0.4 nM	US-10544120: Biaryl kinase inhibitors
(2S)-1-[[6-(7-fluoroquinolin-4-yl)-4-methyl-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.41 nM	US-10351563: Biaryl kinase inhibitors
(S)-8-((2-amino-2,4-dimethylpentyl)oxy)-7-chloro-6H-isochromeno[3,4-c]pyridin-2-amine	IC50	0.41 nM	US-10174044: Fused pyridines as kinase inhibitors
BDBM50243381	IC50	0.42 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[6-(2-chloro-5-fluoro-4-pyridinyl)-4-(difluoromethyl)-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.45 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine	IC50	0.46 nM	US-10351563: Biaryl kinase inhibitors
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-(trifluoromethoxy)phenyl]-2-pyridinyl]acetamide	IC50	0.47 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[6-(7-chloroquinolin-4-yl)-4-methyl-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.47 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[(3-chloro-5-quinolin-4-yl-2-pyridinyl)oxy]-2,4-dimethylpentan-2-amine	IC50	0.49 nM	US-10351563: Biaryl kinase inhibitors
(S)-N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide	IC50	0.49 nM	US-10351563: Biaryl kinase inhibitors
(S)-1-((3-chloro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine	IC50	0.49 nM	US-9902722: Biaryl kinase inhibitors
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-(trifluoromethyl)phenyl]-2-pyridinyl]acetamide	IC50	0.5 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[2-(difluoromethyl)-4-[2-(difluoromethyl)-4-pyridinyl]phenoxy]-2,4-dimethylpentan-2-amine	IC50	0.51 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[4-(6-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine	IC50	0.51 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-4-(difluoromethyl)-2-pyridinyl]-2-pyridinyl]carbamate	IC50	0.51 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[4-(difluoromethyl)-6-(2-methyl-4-pyridinyl)-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.51 nM	US-10351563: Biaryl kinase inhibitors
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-chlorophenyl]-2-pyridinyl]acetamide	IC50	0.53 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[4-(5,7-difluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine	IC50	0.53 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[4-(7-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine	IC50	0.55 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[6-(2-chloro-4-pyridinyl)-4-(difluoromethyl)-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.56 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[4-(6-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine	IC50	0.56 nM	US-10351563: Biaryl kinase inhibitors
(2S)-2,4-dimethyl-1-[[5-quinolin-4-yl-3-(trifluoromethyl)-2-pyridinyl]oxy]pentan-2-amine	IC50	0.59 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-cyanophenyl]-5-fluoro-2-pyridinyl]carbamate	IC50	0.62 nM	US-10351563: Biaryl kinase inhibitors
(S)-ethyl (8-((2-amino-2,4-dimethylpentyl)oxy)-6H-isochromeno[3,4-c]pyridin-2-yl)carbamate	IC50	0.62 nM	US-10174044: Fused pyridines as kinase inhibitors
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-5-fluoropyridin-2-yl)carbamate	IC50	0.62 nM	US-9902722: Biaryl kinase inhibitors
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(difluoromethyl)phenyl]-2-pyridinyl]carbamate	IC50	0.63 nM	US-10351563: Biaryl kinase inhibitors
(2S)-2,4-dimethyl-1-[4-pyridin-4-yl-2-(trifluoromethyl)phenoxy]pentan-2-amine	IC50	0.64 nM	US-10351563: Biaryl kinase inhibitors
(2S)-1-[[3-(difluoromethyl)-5-(5,7-difluoroquinolin-4-yl)-2-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	IC50	0.64 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-cyanophenyl]-2-pyridinyl]carbamate	IC50	0.65 nM	US-10351563: Biaryl kinase inhibitors
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-chloro-2-pyridinyl]-2-pyridinyl]carbamate	IC50	0.65 nM	US-10351563: Biaryl kinase inhibitors
tert-butyl N-[(2S)-1-[4-(7-isocyanoquinolin-4-yl)-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-yl]carbamate	IC50	0.66 nM	US-10155760: Biaryl kinase inhibitors
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)quinoline-7-carbonitrile	IC50	0.66 nM	US-9902722: Biaryl kinase inhibitors

ChEMBL bioactivities

2445 potent at pChembl≥5 of 2462 total, top 23 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.15	IC50	0.07	nM	CHEMBL4085072
10.15	IC50	0.07	nM	CHEMBL5742959
9.72	IC50	0.19	nM	CHEMBL5178245
9.70	IC50	0.2	nM	CHEMBL4544854
9.70	IC50	0.2	nM	CHEMBL5186783
9.70	IC50	0.2	nM	CHEMBL5202896
9.70	IC50	0.2	nM	CHEMBL5783442
9.64	IC50	0.23	nM	CHEMBL4065155
9.62	IC50	0.24	nM	CHEMBL5928143
9.60	IC50	0.25	nM	CHEMBL5842118
9.52	IC50	0.3	nM	CHEMBL4534648
9.52	IC50	0.3	nM	CHEMBL5178261
9.52	IC50	0.3	nM	CHEMBL6064837
9.52	IC50	0.3	nM	CHEMBL5755158
9.51	IC50	0.31	nM	CHEMBL6043665
9.51	IC50	0.31	nM	CHEMBL6047758
9.49	IC50	0.32	nM	CHEMBL4084103
9.49	IC50	0.32	nM	CHEMBL5823275
9.47	IC50	0.34	nM	CHEMBL5178261
9.47	IC50	0.34	nM	CHEMBL5991318
9.44	IC50	0.36	nM	CHEMBL5183016
9.44	IC50	0.36	nM	CHEMBL5796377
9.44	IC50	0.36	nM	CHEMBL5980392

PubChem BioAssay actives

570 with measured affinity, of 1043 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
N-[5-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide	2067008: Binding affinity to AAK1 (unknown origin) assessed as dissociation constant	kd	0.0001	uM
(2S)-1-(2-cyclopropyl-4-quinolin-4-ylphenoxy)-2,4-dimethylpentan-2-amine	1467706: Inhibition of GST-Xa-tagged human AAK1 expressed in bacterial system using fluoresceinated peptide (5 -FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 and ATP incubated for 3 hrs	ic50	0.0001	uM
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-chlorophenyl]-2-pyridinyl]acetamide	1904571: Inhibition of full length human AAK1 expressed in HEK293F cells assessed as suppression of AP2 phosphorylation measured after 3 hrs by Western blot analysis based cellular assay	ic50	0.0002	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(trifluoromethoxy)phenyl]-2-pyridinyl]carbamate	1904571: Inhibition of full length human AAK1 expressed in HEK293F cells assessed as suppression of AP2 phosphorylation measured after 3 hrs by Western blot analysis based cellular assay	ic50	0.0002	uM
(2S)-1-[[3-(difluoromethyl)-5-quinolin-4-yl-2-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	1467706: Inhibition of GST-Xa-tagged human AAK1 expressed in bacterial system using fluoresceinated peptide (5 -FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 and ATP incubated for 3 hrs	ic50	0.0002	uM
(2S)-1-[2-(difluoromethyl)-4-pyrazolo[1,5-a]pyrimidin-7-ylphenoxy]-2,4-dimethylpentan-2-amine	1509581: Inhibition of thrombin-recognition site-fused GST-tagged human AAK1 expressed in bacterial expression system using 5-FAM-Aha-KEEQSQITSQVTGQIGWR-NH2 as substrate after 3 hrs in presence of ATP by fluorescence method	ic50	0.0002	uM
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-cyanophenyl]-2-pyridinyl]acetamide	1509581: Inhibition of thrombin-recognition site-fused GST-tagged human AAK1 expressed in bacterial expression system using 5-FAM-Aha-KEEQSQITSQVTGQIGWR-NH2 as substrate after 3 hrs in presence of ATP by fluorescence method	ic50	0.0003	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-cyclopropylphenyl]-2-pyridinyl]carbamate	1467706: Inhibition of GST-Xa-tagged human AAK1 expressed in bacterial system using fluoresceinated peptide (5 -FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 and ATP incubated for 3 hrs	ic50	0.0003	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(trifluoromethyl)phenyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0003	uM
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-(trifluoromethoxy)phenyl]-2-pyridinyl]acetamide	1904571: Inhibition of full length human AAK1 expressed in HEK293F cells assessed as suppression of AP2 phosphorylation measured after 3 hrs by Western blot analysis based cellular assay	ic50	0.0004	uM
N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(trifluoromethyl)phenyl]-2-pyridinyl]acetamide	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0004	uM
(2S)-1-[2-(difluoromethyl)-4-[2-(difluoromethyl)-4-pyridinyl]phenoxy]-2,4-dimethylpentan-2-amine	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0004	uM
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-(trifluoromethyl)phenyl]-2-pyridinyl]acetamide	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0004	uM
(2S)-1-[2-(difluoromethyl)-4-(2-methyl-4-pyridinyl)phenoxy]-2,4-dimethylpentan-2-amine	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0004	uM
methyl N-[4-[6-[(2S)-2-amino-2,4-dimethylpentoxy]-5-chloro-3-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0004	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-4-(difluoromethyl)-2-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0004	uM
N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-methylphenyl]-2-pyridinyl]acetamide	1467706: Inhibition of GST-Xa-tagged human AAK1 expressed in bacterial system using fluoresceinated peptide (5 -FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 and ATP incubated for 3 hrs	ic50	0.0004	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-4-(trifluoromethyl)-2-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0004	uM
N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(difluoromethyl)phenyl]-2-pyridinyl]acetamide	1904571: Inhibition of full length human AAK1 expressed in HEK293F cells assessed as suppression of AP2 phosphorylation measured after 3 hrs by Western blot analysis based cellular assay	ic50	0.0005	uM
(2S)-1-[[4-(difluoromethyl)-6-[2-(difluoromethyl)-4-pyridinyl]-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	1904571: Inhibition of full length human AAK1 expressed in HEK293F cells assessed as suppression of AP2 phosphorylation measured after 3 hrs by Western blot analysis based cellular assay	ic50	0.0005	uM
(2S)-1-[[4-(difluoromethyl)-6-(2-methyl-4-pyridinyl)-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	1467706: Inhibition of GST-Xa-tagged human AAK1 expressed in bacterial system using fluoresceinated peptide (5 -FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 and ATP incubated for 3 hrs	ic50	0.0005	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-chloro-2-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0005	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(difluoromethyl)phenyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0005	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-cyanophenyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0005	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-chlorophenyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0005	uM
N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-cyanophenyl]-2-pyridinyl]acetamide	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0006	uM
2-[(2S)-2-amino-2,4-dimethylpentoxy]-5-[2-(difluoromethyl)-4-pyridinyl]benzonitrile	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0006	uM
(2S)-2,4-dimethyl-1-[4-pyridin-4-yl-2-(trifluoromethyl)phenoxy]pentan-2-amine	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0006	uM
(2S)-1-[4-[2-(difluoromethyl)-4-pyridinyl]-2-(trifluoromethyl)phenoxy]-2,4-dimethylpentan-2-amine	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0006	uM
ethyl N-[8-[(2S)-2-amino-2,4-dimethylpentoxy]-6H-isochromeno[3,4-c]pyridin-2-yl]carbamate	1509581: Inhibition of thrombin-recognition site-fused GST-tagged human AAK1 expressed in bacterial expression system using 5-FAM-Aha-KEEQSQITSQVTGQIGWR-NH2 as substrate after 3 hrs in presence of ATP by fluorescence method	ic50	0.0006	uM
8-[(2S)-2-amino-4-methylpentoxy]-4,6-dimethyl-5-oxobenzo[c][2,7]naphthyridine-9-carbonitrile	1969353: Inhibition of recombinant AAK1 (unknown origin) expressed in baculovirus assessed as reduction in AP-2 phosphorylation	ic50	0.0006	uM
(2S)-1-[2-cyclopropyl-4-[2-(difluoromethyl)-4-pyridinyl]phenoxy]-2,4-dimethylpentan-2-amine	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0007	uM
2-[(2S)-2-amino-4-methylpentoxy]-5-(2-methyl-4-pyridinyl)benzonitrile	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0008	uM
N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-fluorophenyl]-2-pyridinyl]acetamide	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0008	uM
N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-(trifluoromethoxy)phenyl]-2-pyridinyl]acetamide	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0008	uM
methyl N-[4-[4-[(2S)-2-amino-4-methylpentoxy]-3-(1,2-oxazol-5-yl)phenyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0008	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-(difluoromethyl)-2-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0008	uM
(2S)-1-[[6-(2-chloro-4-pyridinyl)-4-(difluoromethyl)-3-pyridinyl]oxy]-2,4-dimethylpentan-2-amine	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0008	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-methylphenyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0008	uM
N-[8-[(2S)-2-amino-2,4-dimethylpentoxy]-5H-chromeno[3,4-c]pyridin-2-yl]acetamide	1969353: Inhibition of recombinant AAK1 (unknown origin) expressed in baculovirus assessed as reduction in AP-2 phosphorylation	ic50	0.0009	uM
(2S)-2,4-dimethyl-1-[4-(2-methyl-4-pyridinyl)-2-(trifluoromethyl)phenoxy]pentan-2-amine	1826783: Inhibition of GST-Xa tagged human AAK1 (30 to 330 residues) expresssed in bacteria using (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0009	uM
methyl N-[4-[6-[(2S)-2-amino-2,4-dimethylpentoxy]-5-methyl-3-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0009	uM
methyl N-[4-[6-[(2S)-2-amino-2,4-dimethylpentoxy]-5-cyano-3-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0010	uM
N-[(3S)-1-[3-(2-methoxyphenyl)imidazo[1,2-b]pyridazin-6-yl]pyrrolidin-3-yl]-N,2-dimethylpropanamide	1876267: Binding affinity to AAK1 (unknown origin) assessed as dissociation constant	kd	0.0010	uM
N-[(3S)-1-[3-(2-methoxyphenyl)imidazo[1,2-b]pyridazin-6-yl]pyrrolidin-3-yl]-N,2,2-trimethylpropanamide	1876267: Binding affinity to AAK1 (unknown origin) assessed as dissociation constant	kd	0.0010	uM
propan-2-yl N-[(3R)-1-[3-(2-methoxy-3-pyridinyl)imidazo[1,2-b]pyridazin-6-yl]pyrrolidin-3-yl]-N-methylcarbamate	1969357: Binding affinity of AAK1 (unknown origin) assessed as dissociation constant	kd	0.0010	uM
tert-butyl N-[(3R)-1-[3-(2-methoxy-3-pyridinyl)imidazo[1,2-b]pyridazin-6-yl]pyrrolidin-3-yl]-N-methylcarbamate	1969357: Binding affinity of AAK1 (unknown origin) assessed as dissociation constant	kd	0.0010	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide;hydrochloride	1424889: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0010	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-methyl-2-pyridinyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0011	uM
methyl N-[4-[4-[(2S)-2-amino-2,4-dimethylpentoxy]-3-fluorophenyl]-2-pyridinyl]carbamate	1904569: Inhibition of bacterially expressed GST-Xa-tagged human AAK1 using 5-FAM-labelled Aha-KEEQSQITSQVTGQIGWR-NH2 peptide as substrate incubated for 3 hrs in presence of ATP by electrophoretic analysis	ic50	0.0011	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
bisphenol A	decreases methylation, decreases expression, affects expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
perfluorooctanoic acid	increases expression	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
baricitinib	decreases activity	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
decabromobiphenyl ether	decreases expression	1
dimethylselenide	decreases expression, increases expression, increases oxidation	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
perfluorooctane sulfonic acid	increases 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
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1

ChEMBL screening assays

216 unique, capped per target: 216 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1033208	Binding	Inhibition of AAK1 at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1IJ	Abcam HeLa AAK1 KO	Cancer cell line	Female
CVCL_D8YG	Ubigene HEK293 AAK1 KO	Transformed cell line	Female
CVCL_SA85	HAP1 AAK1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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