TNK2

Summary

TNK2 (tyrosine kinase non receptor 2, HGNC:19297) is a protein-coding gene on chromosome 3q29, encoding Activated CDC42 kinase 1 (Q07912). Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation.

This gene encodes a tyrosine kinase that binds Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined.

Source: NCBI Gene 10188 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infantile-onset mesial temporal lobe epilepsy with severe cognitive regression (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 522 total — 1 pathogenic
• Druggable target: yes — 51 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001382273

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19297
Approved symbol	TNK2
Name	tyrosine kinase non receptor 2
Location	3q29
Locus type	gene with protein product
Status	Approved
Aliases	p21cdc42Hs, ACK, ACK1
Ensembl gene	ENSG00000061938
Ensembl biotype	protein_coding
OMIM	606994
Entrez	10188

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 32 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000333602, ENST00000381916, ENST00000428187, ENST00000439230, ENST00000671726, ENST00000671734, ENST00000671753, ENST00000671767, ENST00000671831, ENST00000671880, ENST00000672024, ENST00000672098, ENST00000672145, ENST00000672320, ENST00000672542, ENST00000672548, ENST00000672614, ENST00000672623, ENST00000672669, ENST00000672886, ENST00000672887, ENST00000673038, ENST00000673167, ENST00000673236, ENST00000673358, ENST00000673374, ENST00000673420, ENST00000673440, ENST00000673443, ENST00000673559, ENST00000678220, ENST00000863903, ENST00000863904, ENST00000863905, ENST00000863906, ENST00000863907, ENST00000863908, ENST00000863909, ENST00000863910, ENST00000863911, ENST00000863912, ENST00000863913, ENST00000863914, ENST00000963936

RefSeq mRNA: 24 — MANE Select: NM_001382273 NM_001010938, NM_001308046, NM_001382271, NM_001382272, NM_001382273, NM_001382274, NM_001382275, NM_001386164, NM_001387707, NM_001387708, NM_001387709, NM_001387710, NM_001387711, NM_001387712, NM_001387713, NM_001387714, NM_001387715, NM_001387716, NM_001387717, NM_001387718, NM_001387719, NM_001387720, NM_001387721, NM_005781

CCDS: CCDS33927, CCDS33928, CCDS77875, CCDS93440, CCDS93441, CCDS93442, CCDS93443

Canonical transcript exons

ENST00000672887 — 16 exons

Exon	Start	End
ENSE00001300682	195867361	195868709
ENSE00001770160	195863364	195864187
ENSE00003486553	195883157	195883309
ENSE00003501244	195869497	195869541
ENSE00003559632	195886977	195887047
ENSE00003580768	195879049	195879175
ENSE00003582850	195882051	195882328
ENSE00003593497	195878446	195878592
ENSE00003593985	195866889	195867016
ENSE00003595545	195872276	195872470
ENSE00003605446	195888426	195888606
ENSE00003606558	195878253	195878347
ENSE00003644230	195884812	195885033
ENSE00003650652	195870114	195870205
ENSE00003890660	195908485	195908551
ENSE00003895621	195867169	195867264

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1342 / max 102.2788, expressed in 1582 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46318	2.4529	1018
46312	1.2990	422
46311	0.8649	181
46315	0.6037	314
46319	0.4064	210
46313	0.4027	175
46314	0.0453	9
46320	0.0276	13
46310	0.0223	12
46309	0.0094	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.32	gold quality
right frontal lobe	UBERON:0002810	98.29	gold quality
cerebellar hemisphere	UBERON:0002245	97.96	gold quality
cerebellar cortex	UBERON:0002129	97.91	gold quality
cingulate cortex	UBERON:0003027	97.87	gold quality
anterior cingulate cortex	UBERON:0009835	97.86	gold quality
amygdala	UBERON:0001876	97.66	gold quality
granulocyte	CL:0000094	97.25	gold quality
nucleus accumbens	UBERON:0001882	97.21	gold quality
adenohypophysis	UBERON:0002196	97.05	gold quality
cerebellum	UBERON:0002037	96.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.88	gold quality
pituitary gland	UBERON:0000007	96.85	gold quality
putamen	UBERON:0001874	96.84	gold quality
mucosa of stomach	UBERON:0001199	96.81	gold quality
right uterine tube	UBERON:0001302	96.75	gold quality
lower esophagus mucosa	UBERON:0035834	96.62	gold quality
gastrocnemius	UBERON:0001388	96.47	gold quality
caudate nucleus	UBERON:0001873	96.40	gold quality
sural nerve	UBERON:0015488	96.24	gold quality
prefrontal cortex	UBERON:0000451	96.05	gold quality
skin of abdomen	UBERON:0001416	95.74	gold quality
hypothalamus	UBERON:0001898	95.56	gold quality
muscle of leg	UBERON:0001383	95.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.50	gold quality
neocortex	UBERON:0001950	95.41	gold quality
frontal cortex	UBERON:0001870	95.30	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.25	gold quality
skin of leg	UBERON:0001511	95.23	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.11	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	25.24
E-ANND-3	yes	5.20
E-GEOD-93593	yes	4.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting TNK2, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-6764-3P	98.44	67.64	1153
HSA-MIR-6824-3P	98.44	67.62	1154
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4483	98.09	64.12	1642

Literature-anchored findings (GeneRIF, showing 40)

• ACK-1 and ACK-2 have roles in transducing Cdc42 signals directly to the nucleus (PMID:14733946)
• binding specificity to activated Cdc42-associated kinase is conferred by a specific region in Cdc42 (PMID:15123659)
• crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states (PMID:15308621)
• Data show that in the presence of SNX9, synaptojanin-1 is able to colocalize with distinct ACK1 containing vesicles. (PMID:16137687)
• overexpression of Ack1 in cancer cell lines can increase the invasive phenotype of these cells; Ack1 is involved in extracellular matrix-induced integrin signaling, ultimately activating signaling processes like the activation of the small GTPase Rac (PMID:16247015)
• Ack1 promotes prostate tumorigenesis by tyrosine phosphorylation of tumor suppressor Wwox at Tyr-287. It results in polyubiquitination and degradation of Wwox. (PMID:16288044)
• Molecular chaperone heat shock protein 90beta (Hsp90beta)-bound Ack1 and treatment of prostate cells with geldanamycin, a Hsp90 inhibitor, inhibited Ack1 kinase activity and suppressed prostate tumorigenesis. (PMID:16288044)
• Dimerization in response to EGF and activated Cdc42-associated tyrosine kinase 2 (ACK2), which is mediated by the BAR domain, is essential for the intracellular function of SH3PX1. (PMID:16316319)
• These experiments suggest a functional role for Ack as an early transducer of multiple extracellular stimuli. (PMID:16777958)
• The interaction between Ack1 and p130(Cas) occurred through their respective SH3 domains, while the substrate domain of p130(Cas) was the major site of Ack1-dependent phosphorylation. (PMID:17038317)
• The results were confirmed at the level of mRNA and protein, and suggested that four genes (OPCML, RNASE1, YES1 and ACK1) could play a key role in the tumorigenesis and metastasis of gastric cancer. (PMID:17109515)
• Ack1 activated by surface signals or oncogenic mechanisms may directly enhance AR transcriptional function and promote androgen-independent progression of prostate cancer. (PMID:17494760)
• Ack1 promotes prostate cancer progression to androgen-independence via androgen receptor tyrosine phosphorylation at Tyr-267 and Tyr-363, both sites located within the transactivation domain. (PMID:17494760)
• These data suggest that Ack1 is involved in an early step of EGFR desensitization. (PMID:18262180)
• TNK2 enhanced migration and invasion of breast cancer cells by preserving EGFR expression, inspite of its previously reported signalling via BCAR1, explaining its oncogenic behaviour in vitro and correlation with metastatic human breast cancer in vivo. (PMID:18435854)
• These data define Ack1 as a novel interaction partner of nephrocystin-1 and implicate cell-cell junctions and the renal collecting duct in the pathology of nephronophthisis. (PMID:18477472)
• the interplay between Nedd4-2-related E3 ligases that regulate ACK1 levels and Cbl that modifies EGF receptor impinges on cell receptor dynamics. (PMID:19144635)
• Results identify several receptor tyrosine kinases, including Axl, that can bind to the ACK1/MIG6 homology region. (PMID:19815557)
• These findings suggest an essential role of Nedd4-1 in regulation of EGFR degradation through interaction with and ubiquitination of ACK. (PMID:20086093)
• Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1. (PMID:20110370)
• Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation (PMID:20333297)
• Data show that the ACK1 S985 N mutant is unable to bind ubiquitin, which contributes to ACK1 protein stability and stabilizes EGFR after EGF stimulation, thereby prolonging mitogenic signaling in cancer cells. (PMID:20359967)
• Recent advances in understanding the physiological functions of Ack1 signaling in normal cells and the consequences of its hyperactivation in various cancers, are discussed. (PMID:20432460)
• SNP rs2278034 in ACK1 is associated with IFN therapy outcome in patients with HCV. ACK1 may play a role in innate and IFN-induced antiviral action against HCV. (PMID:21129804)
• ACK1 is not autoinhibited but requires Src for activation. (PMID:21309750)
• The up-regulated expressions of ACK1 protein and mRNA are correlated with the progression and prognosis of esophageal squamous cell carcinoma. (PMID:21418896)
• Ack1 activates AKT directly in pancreatic and other cancer cell lines by phosphorylating AKT at Tyr176 to promote cell survival. (PMID:22322295)
• Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer (PMID:22566699)
• ACK1 directly binds and phosphorylates the Arp2/3 regulatory protein cortactin, potentially providing a direct link to Arp2/3-based actin dynamics during EGFR degradation. (PMID:22952966)
• the molecular mechanisms modulating ACK1 (PMID:23208506)
• Ack1 interacts with Trk receptors and becomes tyrosine phosphorylated and its kinase activity is increased in response to neurotrophins. (PMID:23598414)
• describes a family with severe autosomal recessive infantile onset epilepsy. identified a homozygous missense variant in TNK2. (PMID:23686771)
• Ack1 acts in a kinase-independent manner to promote TRAIL-R1/2 accumulation in lipid rafts. These findings identify Ack1 as an essential player in the spatial regulation of TRAIL-R1/2. (PMID:24085293)
• TNK2 amplification is an independent predictor of a poor prognosis in patients with GC and leads to an increase in the malignant potential of GC cells. (PMID:24178904)
• A novel role for Ack1 in diverting activated EGFR into a non-canonical degradative pathway. (PMID:24413169)
• we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma (PMID:24461128)
• ACK1 interacts with KDM3A to regulate the mammary tumor oncogene HOXA1. (PMID:25148682)
• Increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-beta activity and AKT activation. (PMID:25257795)
• Studies indicate that activated CDC42 kinase 1 (ACK1) interacts with the estrogen receptor (ER) and regulates the activity of androgen receptor (AR) to promote the growth of breast cancer and prostate cancer. (PMID:25347744)
• We uncovered ten new mutations in TNK2 and DDR1 within serous and endometrioid ECs, thus providing novel insights into the mutation spectrum of each gene in EC. (PMID:25427824)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnk2a	ENSDARG00000090646
mus_musculus	Tnk2	ENSMUSG00000022791
rattus_norvegicus	Tnk2	ENSRNOG00000001769
drosophila_melanogaster	Ack	FBGN0028484

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ITK (ENSG00000113263), ZAP70 (ENSG00000115085), PTK2B (ENSG00000120899), SRMS (ENSG00000125508), TEC (ENSG00000135605), BLK (ENSG00000136573), ABL2 (ENSG00000143322), FER (ENSG00000151422), JAK1 (ENSG00000162434), SYK (ENSG00000165025), PTK2 (ENSG00000169398), TNK1 (ENSG00000174292), YES1 (ENSG00000176105), FES (ENSG00000182511), LCK (ENSG00000182866), SRC (ENSG00000197122), LYN (ENSG00000254087)

Protein

Protein identifiers

Activated CDC42 kinase 1 — Q07912 (reviewed: Q07912)

Alternative names: Tyrosine kinase non-receptor protein 2

All UniProt accessions (20): Q07912, A0A499FJ16, A0A5F9ZGX5, A0A5F9ZGY5, A0A5F9ZH01, A0A5F9ZH66, A0A5F9ZHB0, A0A5F9ZHC7, A0A5F9ZHD0, A0A5F9ZHI7, A0A5F9ZHJ2, A0A5F9ZHK8, A0A5F9ZHL4, A0A5F9ZHP4, A0A5F9ZHP9, A0A5F9ZHQ1, A0A5F9ZHX6, A0A5F9ZI29, A0A5F9ZI44, C9J1X3

UniProt curated annotations — full annotation on UniProt →

Function. Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on ‘Tyr-176’. Phosphorylates AR on ‘Tyr-267’ and ‘Tyr-363’ thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on ‘Tyr-287’. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP.

Subunit / interactions. Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4. Homodimer. Interacts with AR, CDC42, WWASL and WWOX. Interacts with CSPG4 (activated). Interacts with MERTK (activated); stimulates autophosphorylation. May interact (phosphorylated) with HSP90AB1; maintains kinase activity. Interacts with NPHP1. Interacts with SNX9 (via SH3 domain). Interacts with SRC (via SH2 and SH3 domain). Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts (via kinase domain) with AKT1. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with BCAR1/p130cas via SH3 domains. Forms complexes with GRB2 and numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by TNK2.

Subcellular location. Cell membrane. Nucleus. Endosome. Cell junction. Adherens junction. Cytoplasmic vesicle membrane. Cytoplasmic vesicle. Clathrin-coated vesicle. Membrane. Clathrin-coated pit. Cytoplasm. Perinuclear region. Cytosol.

Tissue specificity. The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages.

Post-translational modifications. Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits. Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent.

Activity regulation. Inhibited by AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine), which suppresses activating phosphorylation at Tyr-284. Repressed by dasatinib.

Domain organisation. The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR. The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation. The UBA domain binds both poly- and mono-ubiquitin.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q07912-1	1	yes
Q07912-2	2
Q07912-3	3

RefSeq proteins (24): NP_001010938, NP_001294975, NP_001369200, NP_001369201, NP_001369202, NP_001369203, NP_001369204, NP_001373093, NP_001374636, NP_001374637, NP_001374638, NP_001374639, NP_001374640, NP_001374641, NP_001374642, NP_001374643, NP_001374644, NP_001374645, NP_001374646, NP_001374647, NP_001374648, NP_001374649, NP_001374650, NP_005772 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001452	SH3_domain	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015116	Cdc42-bd-like	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR021619	Mig-6	Domain
IPR030220	Ack1_UBA_dom	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037085	Cdc42-bd-like_dom_sf	Homologous_superfamily
IPR049587	TNK-like_SAM	Domain
IPR052112	EGFR_SigReg_Kinase	Family
IPR055175	ACK/TNK-like_SAM	Domain

Pfam: PF07714, PF09027, PF11555, PF14604, PF22931

Enzyme classification (BRENDA):

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• 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 (97 total): strand 20, helix 16, sequence variant 13, region of interest 9, modified residue 8, sequence conflict 6, splice variant 5, mutagenesis site 5, domain 4, turn 4, compositionally biased region 3, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4HZR	X-RAY DIFFRACTION	1.31
8THA	X-RAY DIFFRACTION	1.68
7KP6	X-RAY DIFFRACTION	1.79
8Q5P	X-RAY DIFFRACTION	1.81
1U46	X-RAY DIFFRACTION	2
3EQR	X-RAY DIFFRACTION	2
1U4D	X-RAY DIFFRACTION	2.1
5ZXB	X-RAY DIFFRACTION	2.2
3EQP	X-RAY DIFFRACTION	2.3
4EWH	X-RAY DIFFRACTION	2.5
8FZ3	X-RAY DIFFRACTION	2.78
1U54	X-RAY DIFFRACTION	2.8
6VQM	X-RAY DIFFRACTION	2.87
4ID7	X-RAY DIFFRACTION	3
8HMT	X-RAY DIFFRACTION	3.17
8FE9	X-RAY DIFFRACTION	3.2
4HZS	X-RAY DIFFRACTION	3.23
1CF4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07912-F1	62.41	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): 252 (proton acceptor)

Ligand- & substrate-binding residues (2): 132–140; 158

Post-translational modifications (8): 284, 518, 724, 827, 839, 859, 872, 881

Mutagenesis-validated functional residues (5):

Position	Phenotype
120	no effect on autophosphorylation at y-284.
158	loss of autophosphorylation at y-284.
197	no effect on autophosphorylation at y-284.
365	increased autophosphorylation at y-284.
487	constantly active kinase.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9842663	Signaling by LTK
R-HSA-162582	Signal Transduction
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 237 (showing top): GGGACCA_MIR133A_MIR133B, WANG_CLIM2_TARGETS_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GATA6_01, GOCC_COATED_VESICLE, GOBP_REGULATION_OF_ENDOCYTOSIS, MAGRANGEAS_MULTIPLE_MYELOMA_IGLL_VS_IGLK_UP, MARSON_FOXP3_TARGETS_UP

GO Biological Process (8): endocytosis (GO:0006897), cell surface receptor signaling pathway (GO:0007166), small GTPase-mediated signal transduction (GO:0007264), phosphorylation (GO:0016310), positive regulation of peptidyl-tyrosine phosphorylation (GO:0050731), regulation of clathrin-dependent endocytosis (GO:2000369), protein phosphorylation (GO:0006468), signal transduction (GO:0007165)

GO Molecular Function (17): protein serine/threonine kinase activity (GO:0004674), protein serine/threonine/tyrosine kinase activity (GO:0004712), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), GTPase inhibitor activity (GO:0005095), epidermal growth factor receptor binding (GO:0005154), ATP binding (GO:0005524), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), metal ion binding (GO:0046872), WW domain binding (GO:0050699), 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 (15): nucleus (GO:0005634), cytoplasm (GO:0005737), endosome (GO:0005768), cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), adherens junction (GO:0005912), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), cytoplasmic vesicle membrane (GO:0030659), perinuclear region of cytoplasm (GO:0048471), Grb2-EGFR complex (GO:0070436), cytoophidium (GO:0097268), cytoplasmic vesicle (GO:0031410), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	4
cellular anatomical structure	4
cytoplasm	3
endomembrane system	2
cytoplasmic vesicle	2
membrane	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
signal transduction	1
intracellular signaling cassette	1
phosphate-containing compound metabolic process	1
positive regulation of protein phosphorylation	1
peptidyl-tyrosine phosphorylation	1
regulation of peptidyl-tyrosine phosphorylation	1
regulation of receptor-mediated endocytosis	1
clathrin-dependent endocytosis	1
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein tyrosine kinase activity	1
GTPase activity	1
enzyme inhibitor activity	1
GTPase regulator activity	1
growth factor receptor binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ubiquitin-like protein ligase binding	1
protein binding	1
cation binding	1
protein domain specific binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1

Protein interactions and networks

STRING

1090 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNK2	CDC42	P21181	984
TNK2	NEDD4L	Q96PU5	822
TNK2	HSH2D	Q96JZ2	768
TNK2	WAS	P42768	747
TNK2	WWOX	Q9NZC7	688
TNK2	HCK	P08631	664
TNK2	AR	P10275	655
TNK2	BCAR1	P56945	627
TNK2	NCK1	P16333	617
TNK2	GRB2	P29354	613
TNK2	MCF2	P10911	604
TNK2	NEDD4	P46934	582
TNK2	CLTCL1	P53675	568
TNK2	WASL	O00401	561
TNK2	CLTC	Q00610	545

IntAct

90 interactions, top by confidence:

A	B	Type	Score
GRB2	TNK2	psi-mi:“MI:0407”(direct interaction)	0.800
TNK2	GRB2	psi-mi:“MI:0407”(direct interaction)	0.800
GRB2	TNK2	psi-mi:“MI:0915”(physical association)	0.800
NCK1	TNK2	psi-mi:“MI:0407”(direct interaction)	0.760
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
CLTC	TNK2	psi-mi:“MI:0407”(direct interaction)	0.700
TNK2	CLTC	psi-mi:“MI:0915”(physical association)	0.700
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
TNK2	TNK2	psi-mi:“MI:0915”(physical association)	0.590
CDC42	TNK2	psi-mi:“MI:0407”(direct interaction)	0.590
CDC42	TNK2	psi-mi:“MI:0915”(physical association)	0.590
TNK2	TNK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.590
SH2D1A	TNK2	psi-mi:“MI:0915”(physical association)	0.560
TNK2	GALT	psi-mi:“MI:0915”(physical association)	0.560
TNK2	AQP1	psi-mi:“MI:0915”(physical association)	0.560
TNK2	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
	TNK2	psi-mi:“MI:0915”(physical association)	0.560
NEK6	TNK2	psi-mi:“MI:0915”(physical association)	0.560
GALT	TNK2	psi-mi:“MI:0915”(physical association)	0.560
TNK2		psi-mi:“MI:0915”(physical association)	0.560
TNK2	NEK6	psi-mi:“MI:0915”(physical association)	0.560
TNK2	SH2D1A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (270): TNK2 (Affinity Capture-Western), TRIM50 (Affinity Capture-Western), TNK2 (Two-hybrid), TNK2 (Two-hybrid), TNK2 (Two-hybrid), TNK2 (Two-hybrid), NEK6 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), TNK2 (Affinity Capture-Western), Nedd4l (Reconstituted Complex), Amph (Reconstituted Complex), Clta (Reconstituted Complex), Fabp4 (Reconstituted Complex), Bin2 (Reconstituted Complex)

ESM2 similar proteins: A0JPN4, A2A288, A2ARK0, A6ND36, A6QQJ8, A7E316, E9Q0S6, E9Q2Z1, O15037, O54714, O54967, O70260, O70405, O75385, O94983, P42335, P48778, Q07912, Q0P4K8, Q17R13, Q1LVK9, Q32PJ7, Q4V8I3, Q5D1E7, Q5D1E8, Q5DTV4, Q5HYM0, Q5JV73, Q5SWY7, Q5SXM2, Q5U2X5, Q5XIS1, Q68CZ2, Q6A037, Q6IRU7, Q6P1H6, Q6S5L8, Q7TP65, Q7TSG2, Q80U38

Diamond homologs: A0JNB0, A1Y2K1, F1N9Y5, G5EBZ8, G5ECJ6, O35346, O45539, O54967, P00519, P00520, P00521, P00522, P00523, P00524, P00525, P00530, P00533, P00534, P00535, P00541, P00542, P03949, P05480, P06239, P06240, P06241, P08103, P08630, P08631, P09760, P09769, P10447, P11273, P12931, P13115, P13116, P13388, P14084, P14085, P14234

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
TNK2	up-regulates	TNK2	phosphorylation
TNK2	up-regulates	SNX9	phosphorylation
TNK2	“down-regulates activity”	KDM3A	phosphorylation
PDGFRB	“up-regulates activity”	TNK2	phosphorylation
TNK2	“up-regulates activity”	AR	phosphorylation
TNK2	“up-regulates activity”	STAT1	phosphorylation
SRC	“up-regulates activity”	TNK2	phosphorylation
TNK2	“up-regulates activity”	WWP2	phosphorylation
TNK2	“up-regulates activity”	STAT3	phosphorylation
TNK2	“up-regulates activity”	WASL	phosphorylation
TNK2	“up-regulates activity”	AKT1	phosphorylation
TNK2	“up-regulates activity”	AKT	phosphorylation
TNK2	“up-regulates activity”	TNK2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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
Downstream signal transduction	5	46.4×	5e-06
EGFR downregulation	5	42.2×	7e-06
RHOU GTPase cycle	6	40.8×	7e-07
Regulation of actin dynamics for phagocytic cup formation	8	35.9×	2e-08
RHOV GTPase cycle	5	34.8×	2e-05
FCGR3A-mediated phagocytosis	7	32.0×	3e-07
VEGFA-VEGFR2 Pathway	7	23.8×	1e-06
Clathrin-mediated endocytosis	9	18.7×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
T cell activation	5	27.6×	4e-04
epidermal growth factor receptor signaling pathway	5	26.4×	4e-04
actin filament organization	6	15.2×	6e-04
positive regulation of MAPK cascade	5	8.6×	9e-03
negative regulation of apoptotic process	8	5.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	322
Likely benign	112
Benign	44

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1334415	NM_001382273.1(TNK2):c.1054C>T (p.Arg352Trp)	Pathogenic

SpliceAI

4318 predictions. Top by Δscore:

Variant	Effect	Δscore
3:195868706:GGTT:G	acceptor_gain	1.0000
3:195868707:GTTCT:G	acceptor_loss	1.0000
3:195868708:TT:T	acceptor_gain	1.0000
3:195868708:TTCT:T	acceptor_loss	1.0000
3:195868709:TCTGT:T	acceptor_loss	1.0000
3:195868710:C:CA	acceptor_loss	1.0000
3:195868710:C:CC	acceptor_gain	1.0000
3:195868711:T:A	acceptor_loss	1.0000
3:195868712:G:C	acceptor_gain	1.0000
3:195868715:A:AC	acceptor_gain	1.0000
3:195868715:A:C	acceptor_gain	1.0000
3:195870112:A:AC	donor_gain	1.0000
3:195870113:C:CC	donor_gain	1.0000
3:195872268:GTACT:G	donor_loss	1.0000
3:195872271:CTCA:C	donor_gain	1.0000
3:195872272:TCA:T	donor_loss	1.0000
3:195872273:CACT:C	donor_loss	1.0000
3:195872274:A:AC	donor_gain	1.0000
3:195872274:ACT:A	donor_gain	1.0000
3:195872275:C:CT	donor_gain	1.0000
3:195872275:CT:C	donor_gain	1.0000
3:195872275:CTC:C	donor_gain	1.0000
3:195872275:CTCG:C	donor_gain	1.0000
3:195872275:CTCGT:C	donor_gain	1.0000
3:195872469:CC:C	acceptor_gain	1.0000
3:195872469:CCCT:C	acceptor_loss	1.0000
3:195872470:CC:C	acceptor_gain	1.0000
3:195872470:CCTGC:C	acceptor_loss	1.0000
3:195872471:C:CA	acceptor_loss	1.0000
3:195872472:T:A	acceptor_loss	1.0000

AlphaMissense

6823 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:195872414:A:G	F438S	1.000
3:195872447:C:T	G427D	1.000
3:195872454:A:G	W425R	1.000
3:195872454:A:T	W425R	1.000
3:195878265:A:T	V415D	1.000
3:195878465:A:G	L381P	1.000
3:195878482:T:A	R375S	1.000
3:195878482:T:G	R375S	1.000
3:195878483:C:G	R375T	1.000
3:195878505:A:G	W368R	1.000
3:195878505:A:T	W368R	1.000
3:195878506:G:C	C367W	1.000
3:195878508:A:G	C367R	1.000
3:195879072:A:G	W331R	1.000
3:195879072:A:T	W331R	1.000
3:195879074:G:T	P330H	1.000
3:195879098:T:A	E322V	1.000
3:195879102:A:G	W321R	1.000
3:195879102:A:T	W321R	1.000
3:195879104:A:G	L320P	1.000
3:195879113:C:T	G317E	1.000
3:195879114:C:A	G317W	1.000
3:195879114:C:G	G317R	1.000
3:195879114:C:T	G317R	1.000
3:195879121:C:A	W314C	1.000
3:195879121:C:G	W314C	1.000
3:195879123:A:G	W314R	1.000
3:195879123:A:T	W314R	1.000
3:195879128:T:A	D312V	1.000
3:195879128:T:C	D312G	1.000

dbSNP variants (sampled 300 via entrez): RS1000045789 (3:195908735 C>T), RS1000048004 (3:195875692 G>A), RS1000052264 (3:195877849 C>T), RS1000062534 (3:195866052 T>C), RS1000157355 (3:195875572 C>G,T), RS1000317195 (3:195871598 G>A), RS1000368811 (3:195886018 C>T), RS1000451626 (3:195880135 G>A), RS1000464801 (3:195869319 CGGG>C,CGG,CGGGG), RS1000475006 (3:195910262 G>C,T), RS1000484620 (3:195886239 C>A), RS1000495582 (3:195873852 G>A), RS1000605364 (3:195907392 C>A), RS1000606345 (3:195880419 C>A), RS1000775606 (3:195871524 G>A,C,T)

Disease associations

OMIM: gene MIM:606994 | disease phenotypes: MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
infantile-onset mesial temporal lobe epilepsy with severe cognitive regression	Supportive	Autosomal recessive
genetic generalized epilepsy	Limited	Autosomal recessive

Mondo (4): developmental and epileptic encephalopathy (MONDO:0100620), Parkinson disease (MONDO:0005180), infantile-onset mesial temporal lobe epilepsy with severe cognitive regression (MONDO:0018314), genetic generalized epilepsy (MONDO:0100575)

Orphanet (1): NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002104_17	Bronchopulmonary dysplasia	5.000000e-06
GCST007203_13	Total cholesterol levels	5.000000e-06
GCST007204_7	Low density lipoprotein cholesterol levels	3.000000e-06
GCST009798_62	Asthma	2.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4599 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

51 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 231,640 (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
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3286830	LORLATINIB	4	3,598
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL3622821	UPADACITINIB	4	2,726
CHEMBL3889654	LAROTRECTINIB	4	1,850
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4
CHEMBL939	GEFITINIB	4
CHEMBL217092	SARACATINIB	3
CHEMBL483158	ALISERTIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2
CHEMBL1231124	AZD-1480	2
CHEMBL1721885	SU-014813	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 — Ack family

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
compound 30 [PMID: 17280833]	Inhibition	9.0	pIC50
bosutinib	Inhibition	8.57	pIC50
NIK inhibitor 12f	Inhibition	6.72	pIC50

Binding affinities (BindingDB)

284 measured of 368 human assays (368 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
5-chloro-2-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-4-N-[2-(2-methoxyphenyl)ethyl]pyrimidine-2,4-diamine	IC50	2 nM	US-10336734: Inhibitors of ACK1/TNK2 tyrosine kinase
5-chloro-4-N-[2-(2-chloro-6-fluorophenyl)ethyl]-2-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine	IC50	7 nM	US-10336734: Inhibitors of ACK1/TNK2 tyrosine kinase
3-phenyl-2-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-N-[2-(pyridin-3-yl)ethyl]furo[2,3-b]pyridin-4-amine	IC50	20 nM
[4-[8-amino-3-[4-(4-methylpiperazin-1-yl)phenyl]imidazo[1,5-a]pyrazin-1-yl]-2-methoxyphenyl]-phenylmethanone	IC50	30 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
4-(4-fluorophenyl)-3-pyridin-4-yl-1-(2,4,6-trichlorophenyl)pyrazol-5-amine	IC50	33 nM	US-9416123: Kinase modulators for the treatment of cancer
5-chloro-2-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-4-N-[[(2R)-oxolan-2-yl]methyl]pyrimidine-2,4-diamine	IC50	34 nM	US-10336734: Inhibitors of ACK1/TNK2 tyrosine kinase
[4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl]-phenylmethanone	IC50	35.2 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[2-amino-4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)phenyl]-phenylmethanone	IC50	36.9 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[4-[2-(dimethylamino)ethoxy]phenyl]-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	43.9 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-cyclobutyl-1-(3-methoxy-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	48.7 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[8-amino-1-[4-(oxan-2-yloxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]cyclobutan-1-ol	IC50	50 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[2-amino-4-[8-amino-3-(3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl]phenyl]-phenylmethanone	IC50	50 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
5-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenoxyphenol	IC50	58.9 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl]-phenylmethanone	IC50	60.4 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[4-(4-methylpiperazin-1-yl)phenyl]-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	66.7 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-cyclobutyl-1-(2-methoxy-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	75 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[4-[(dimethylamino)methyl]cyclohexyl]-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	75.1 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
2-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-3-phenyl-N-[2-(piperazin-1-yl)ethyl]furo[2,3-b]pyridin-4-amine	IC50	84 nM
[4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)phenyl]-phenylmethanone	IC50	86.5 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-cyclobutyl-1-(3-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	88 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[4-[8-amino-3-(3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl]-phenylmethanone	IC50	88.6 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
1-[4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)phenyl]-1-phenylethanol	IC50	90 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-cyclobutyl-1-[4-(2-fluorophenoxy)phenyl]imidazo[1,5-a]pyrazin-8-amine	IC50	95.2 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
1-(4-phenoxyphenyl)-3-propan-2-ylimidazo[1,5-a]pyrazin-8-amine	IC50	95.8 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-cyclobutyl-1-[4-(3-fluorophenoxy)phenyl]imidazo[1,5-a]pyrazin-8-amine	IC50	109 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
1-(3-amino-4-phenoxyphenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine	IC50	110 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
N-[(2S)-oxolan-2-ylmethyl]-2,3-diphenylfuro[2,3-b]pyridin-4-amine	IC50	110 nM
[4-[8-amino-3-(3-hydroxycyclobutyl)imidazo[1,5-a]pyrazin-1-yl]phenyl]-phenylmethanone	IC50	112 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[8-amino-1-(3-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol	IC50	115 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[4-[8-amino-3-(3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl]-2-methoxyphenyl]-phenylmethanone	IC50	117 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[8-amino-1-(2-methoxy-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol	IC50	119 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-phenyl-N-[2-(piperazin-1-yl)ethyl]-2-{4-[2-(piperidin-1-yl)ethoxy]phenyl}furo[2,3-b]pyridin-4-amine	IC50	120 nM
US8481733, 159	IC50	122 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[4-(4-amino-7-cyclobutylimidazo[5,1-f][1,2,4]triazin-5-yl)-3-fluorophenyl]-phenylmethanone	IC50	136 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol	IC50	137 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl]methanol	IC50	139 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[4-[8-amino-3-(3-hydroxy-3-methylcyclobutyl)imidazo[1,5-a]pyrazin-1-yl]-2-fluorophenyl]-phenylmethanone	IC50	140 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-(furan-3-yl)-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	145 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-cyclobutyl-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	148 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
2-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-3-phenyl-N-[2-(piperazin-1-yl)ethyl]furo[2,3-b]pyridin-4-amine	IC50	150 nM
3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutan-1-ol	IC50	153 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[4-(methylaminomethyl)cyclohexyl]-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine	IC50	154 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-phenyl-N-[2-(piperazin-1-yl)ethyl]-2-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}furo[2,3-b]pyridin-4-amine	IC50	170 nM
7-[4-(aminomethyl)cyclohexyl]-5-(4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine	IC50	176 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
3-[8-amino-1-[4-(oxan-2-yloxy)phenyl]imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol	IC50	178 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
2-(4-{2-[bis(propan-2-yl)amino]ethoxy}phenyl)-3-phenyl-N-[2-(piperazin-1-yl)ethyl]furo[2,3-b]pyridin-4-amine	IC50	180 nM
3-phenyl-2-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-N-[2-(pyridin-4-yl)ethyl]furo[2,3-b]pyridin-4-amine	IC50	180 nM
[4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-3-chlorophenyl]-phenylmethanone	IC50	181 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines
[4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl]-phenylmethanone	IC50	181 nM	US-8481733: Substituted imidazopyr- and imidazotri-azines

ChEMBL bioactivities

908 potent at pChembl≥5 of 940 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	Ki	0.2	nM	CHEMBL2087874
9.70	IC50	0.2	nM	CHEMBL5400397
9.52	Ki	0.3	nM	CHEMBL2087873
9.52	Ki	0.3	nM	CHEMBL2087875
9.52	Ki	0.3	nM	CHEMBL2087874
9.52	IC50	0.3	nM	CHEMBL5408748
9.52	IC50	0.3	nM	CHEMBL5431206
9.40	IC50	0.4	nM	CHEMBL5409024
9.22	IC50	0.6	nM	CHEMBL5398945
9.22	IC50	0.6	nM	CHEMBL5428907
9.22	IC50	0.6	nM	CHEMBL5419830
9.15	IC50	0.7	nM	CHEMBL5405674
9.15	IC50	0.7	nM	CHEMBL5399309
9.10	IC50	0.8	nM	CHEMBL5437496
9.10	Ki	0.7943	nM	TAE-684
9.05	IC50	0.9	nM	CHEMBL5439245
9.04	IC50	0.92	nM	CHEMBL5772004
9.02	IC50	0.95	nM	CHEMBL6022678
9.00	IC50	1	nM	CHEMBL247667
9.00	IC50	1	nM	DASATINIB
9.00	IC50	1	nM	CHEMBL5436567
8.96	IC50	1.1	nM	CHEMBL5434969
8.90	IC50	1.26	nM	CHEMBL5853387
8.90	Ki	1.259	nM	PD-0166285
8.89	IC50	1.3	nM	CHEMBL5431312
8.88	IC50	1.32	nM	CHEMBL5968204
8.88	IC50	1.31	nM	CHEMBL5756581
8.86	IC50	1.38	nM	CHEMBL6054797
8.83	IC50	1.48	nM	NESUPARIB
8.80	Ki	1.585	nM	CHEMBL1980995
8.78	IC50	1.65	nM	CHEMBL5795408
8.76	IC50	1.75	nM	CHEMBL5932989
8.76	IC50	1.75	nM	CHEMBL5822783
8.73	IC50	1.87	nM	CHEMBL5997953
8.72	IC50	1.9	nM	CHEMBL5404048
8.71	IC50	1.97	nM	CHEMBL6058132
8.71	IC50	1.96	nM	CHEMBL6001595
8.70	Ki	2	nM	CHEMBL2087652
8.70	Ki	2	nM	CHEMBL2087654
8.70	Ki	2	nM	CHEMBL2087662
8.70	IC50	2	nM	CHEMBL487242
8.70	Kd	2	nM	CHEMBL1672987
8.70	Ki	2	nM	CHEMBL472392
8.70	Ki	2	nM	CHEMBL487897
8.70	Ki	2	nM	CHEMBL504331
8.70	IC50	1.99	nM	CHEMBL5924751
8.70	Kd	2	nM	TAE-684
8.68	IC50	2.1	nM	CHEMBL5415503
8.68	IC50	2.1	nM	CHEMBL6023648
8.67	IC50	2.12	nM	CHEMBL5879210

PubChem BioAssay actives

456 with measured affinity, of 1834 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
6-[4-[2-(dimethylamino)ethoxy]phenyl]-N-(1,3-dithiolan-2-ylmethyl)-5-phenylfuro[2,3-d]pyrimidin-4-amine	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0002	uM
6-(2-chlorophenyl)-2-[4-[4-(dimethylamino)piperidin-1-yl]-3-methylanilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0002	uM
6-[4-[2-(dimethylamino)ethoxy]phenyl]-N-(1,3-dithiolan-2-ylmethyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0003	uM
N-(1,3-dithiolan-2-ylmethyl)-5-phenyl-6-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0003	uM
6-(2-chlorophenyl)-2-[3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0003	uM
6-(2-chlorophenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0003	uM
6-(2-chlorophenyl)-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0004	uM
2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-6-(2-methylphenyl)-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0006	uM
N-[3-[2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0006	uM
6-(2-chlorophenyl)-2-[3-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0006	uM
6-(2-chlorophenyl)-2-[2-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0007	uM
2-[3-chloro-4-(4-methylpiperazin-1-yl)anilino]-6-(2-chlorophenyl)-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0007	uM
6-(2-chlorophenyl)-2-[4-[4-(2-hydroxyethyl)piperazin-1-yl]-3-methylanilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0008	uM
6-(2-chlorophenyl)-2-[3-cyclopentyloxy-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0009	uM
5-phenyl-N-(2-phenylethyl)-6-[4-(2-pyrrolidin-1-ylethoxy)phenyl]furo[2,3-d]pyrimidin-4-amine	306431: Inhibition of Ack1	ic50	0.0010	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	1961418: Inhibition of ACK1 (unknown origin)	ic50	0.0010	uM
6-(2-chlorophenyl)-2-[4-(4-methylpiperazin-1-yl)-3-propan-2-yloxyanilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0010	uM
6-(2-chlorophenyl)-2-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0011	uM
6-(2-bromophenyl)-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0013	uM
6-(2-chlorophenyl)-2-(3-methylanilino)-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0019	uM
3-N-(2,6-dimethylphenyl)-1-(3-methoxy-3-methylbutyl)-6-N-(4-piperazin-1-ylphenyl)pyrazolo[3,4-d]pyrimidine-3,6-diamine	411382: Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells	ki	0.0020	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624807: Binding constant for TNK2 kinase domain	kd	0.0020	uM
3-N-(2,6-dichlorophenyl)-6-N-[3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1-(3-methoxy-3-methylbutyl)pyrazolo[3,4-d]pyrimidine-3,6-diamine	411382: Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells	ki	0.0020	uM
3-N-(2,6-dimethylphenyl)-1-(3-methoxy-3-methylbutyl)-6-N-phenylpyrazolo[3,4-d]pyrimidine-3,6-diamine	1205061: Inhibition of ACK1 kinase (unknown origin)	ic50	0.0020	uM
3-N-(2,6-dimethylphenyl)-1-(3-methoxy-3-methylbutyl)-6-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrazolo[3,4-d]pyrimidine-3,6-diamine	411382: Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells	ki	0.0020	uM
2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-11-methyl-5H-pyrimido[4,5-b][1,4]benzodiazepin-6-one	1205061: Inhibition of ACK1 kinase (unknown origin)	kd	0.0020	uM
N,N-dimethyl-4-[4-[[(2S)-oxolan-2-yl]methylamino]-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzenesulfonamide	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0020	uM
N,N-dimethyl-4-[4-[[(2S)-oxolan-2-yl]methylamino]-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzamide	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0020	uM
N-methyl-4-[4-[[(2S)-oxolan-2-yl]methylamino]-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzenesulfonamide	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0020	uM
N-[3-[2-[2-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0021	uM
6-(2-fluorophenyl)-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0026	uM
Bosutinib	1205061: Inhibition of ACK1 kinase (unknown origin)	ic50	0.0027	uM
2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-6-(2-nitrophenyl)-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0028	uM
3-N-(2,6-dimethylphenyl)-6-N-[3-fluoro-4-(3-piperidin-1-ylpropoxy)phenyl]-1-(3-methoxy-3-methylbutyl)pyrazolo[3,4-d]pyrimidine-3,6-diamine	411382: Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells	ki	0.0030	uM
N-[3-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0030	uM
3-N-(2,6-dimethylphenyl)-1-(3-methoxy-3-methylbutyl)-6-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyrazolo[3,4-d]pyrimidine-3,6-diamine	411382: Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells	ki	0.0030	uM
3-N-(2,6-dimethylphenyl)-6-N-[3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1-(3-methoxy-3-methylbutyl)pyrazolo[3,4-d]pyrimidine-3,6-diamine	411382: Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells	ki	0.0030	uM
N-methyl-4-[4-[[(2S)-oxolan-2-yl]methylamino]-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzamide	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0030	uM
6-(2-iodophenyl)-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1988518: Inhibition of N-terminal His6-tagged ACK1 (117 to 389 residues) (unknown origin) expressed in Sf9 cells using ATP as substrate incubated for 1 hrs by ELISA	ic50	0.0035	uM
2-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]-11-methyl-5H-pyrimido[4,5-b][1,4]benzodiazepin-6-one	1651365: Inhibition of tracer 236 binding to recombinant human GST-tagged TNK2 catalytic domain (110 to 476 residues) expressed in baculovirus expression system incubated for 60 mins by Lanthascreen assay	ic50	0.0040	uM
2-[3-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-11-methyl-5H-pyrimido[4,5-b][1,4]benzodiazepin-6-one	1651365: Inhibition of tracer 236 binding to recombinant human GST-tagged TNK2 catalytic domain (110 to 476 residues) expressed in baculovirus expression system incubated for 60 mins by Lanthascreen assay	ic50	0.0040	uM
2-[4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methoxyanilino]-11-methyl-5H-pyrimido[4,5-b][1,4]benzodiazepin-6-one	1651365: Inhibition of tracer 236 binding to recombinant human GST-tagged TNK2 catalytic domain (110 to 476 residues) expressed in baculovirus expression system incubated for 60 mins by Lanthascreen assay	ic50	0.0040	uM
6-[4-(2-morpholin-4-ylethoxy)phenyl]-N-[[(2S)-oxolan-2-yl]methyl]-5-phenylfuro[2,3-d]pyrimidin-4-amine	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0040	uM
1-[2-[4-[4-[[(2S)-oxolan-2-yl]methylamino]-5-phenylfuro[2,3-d]pyrimidin-6-yl]phenoxy]ethyl]pyrrolidin-2-one	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0040	uM
5-(2-fluorophenyl)-N-[[(2S)-oxolan-2-yl]methyl]-6-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0040	uM
6-[4-[2-(dimethylamino)ethoxy]phenyl]-N-(1,3-dithian-2-ylmethyl)-5-phenylfuro[2,3-d]pyrimidin-4-amine	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0040	uM
N-methyl-4-[4-[[(2S)-oxolan-2-yl]methylamino]-5-phenylfuro[2,3-d]pyrimidin-6-yl]benzenesulfonamide	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0040	uM
1-[2-[4-[4-[[(2S)-oxolan-2-yl]methylamino]-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenoxy]ethyl]pyrrolidin-2-one	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0040	uM
2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)-1,3,5-triazine-2,4-diamine	1425201: 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	0.0050	uM
6-[4-[2-(dimethylamino)ethoxy]phenyl]-N-[[(2S)-oxolan-2-yl]methyl]-5-phenylfuro[2,3-d]pyrimidin-4-amine	682952: Inhibition of N-terminal His6-tagged ACK1 expressed in baculovirus infected Hi5 cells assessed as inhibition of autophosphorylation after 2 hrs by ELISA	ki	0.0050	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression, decreases expression (+1 more)	4
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects methylation	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
abrine	decreases expression	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases expression	1
Caffeine	decreases phosphorylation	1
Diethylstilbestrol	increases expression	1
Drugs, Chinese Herbal	decreases activity	1
Estradiol	decreases expression	1
Flavonoids	increases expression	1
Ivermectin	decreases expression	1
Lead	affects expression, affects splicing	1
Methylcholanthrene	affects binding, increases reaction	1
Plant Extracts	increases expression	1
Smoke	increases expression	1

ChEMBL screening assays

348 unique, capped per target: 346 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1017265	Binding	Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells	Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors. — Bioorg Med Chem Lett
CHEMBL1963777	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ACK1	PubChem BioAssay data set

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1ZD	Abcam A-549 TNK2 KO	Cancer cell line	Male
CVCL_D2DE	Abcam HCT 116 TNK2 KO	Cancer cell line	Male
CVCL_TT15	HAP1 TNK2 (-)	Cancer cell line	Male

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