PTK2B

Summary

PTK2B (protein tyrosine kinase 2 beta, HGNC:9612) is a protein-coding gene on chromosome 8p21.2, encoding Protein-tyrosine kinase 2-beta (Q14289). Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling.

This gene encodes a cytoplasmic protein tyrosine kinase which is involved in calcium-induced regulation of ion channels and activation of the map kinase signaling pathway. The encoded protein may represent an important signaling intermediate between neuropeptide-activated receptors or neurotransmitters that increase calcium flux and the downstream signals that regulate neuronal activity. The encoded protein undergoes rapid tyrosine phosphorylation and activation in response to increases in the intracellular calcium concentration, nicotinic acetylcholine receptor activation, membrane depolarization, or protein kinase C activation. This protein has been shown to bind CRK-associated substrate, nephrocystin, GTPase regulator associated with FAK, and the SH2 domain of GRB2. The encoded protein is a member of the FAK subfamily of protein tyrosine kinases but lacks significant sequence similarity to kinases from other subfamilies. Four transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 2185 — RefSeq curated summary.

At a glance

• GWAS associations: 29
• Clinical variants (ClinVar): 183 total
• Druggable target: yes — 43 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_173176

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9612
Approved symbol	PTK2B
Name	protein tyrosine kinase 2 beta
Location	8p21.2
Locus type	gene with protein product
Status	Approved
Aliases	CAKB, PYK2, RAFTK, PTK, CADTK
Ensembl gene	ENSG00000120899
Ensembl biotype	protein_coding
OMIM	601212
Entrez	2185

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 38 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000346049, ENST00000397497, ENST00000397501, ENST00000412793, ENST00000420218, ENST00000461615, ENST00000482543, ENST00000495097, ENST00000496920, ENST00000517339, ENST00000519512, ENST00000519650, ENST00000521000, ENST00000521164, ENST00000522245, ENST00000522338, ENST00000522517, ENST00000894136, ENST00000894137, ENST00000894138, ENST00000894139, ENST00000894140, ENST00000894141, ENST00000894142, ENST00000894143, ENST00000894144, ENST00000894145, ENST00000894146, ENST00000894147, ENST00000894148, ENST00000894149, ENST00000894150, ENST00000894151, ENST00000894152, ENST00000894153, ENST00000894154, ENST00000913748, ENST00000913749, ENST00000913750, ENST00000913751, ENST00000956521, ENST00000956522, ENST00000956523, ENST00000956524, ENST00000956525, ENST00000956526

RefSeq mRNA: 4 — MANE Select: NM_173176 NM_004103, NM_173174, NM_173175, NM_173176

CCDS: CCDS6057, CCDS6058

Canonical transcript exons

ENST00000346049 — 31 exons

Exon	Start	End
ENSE00000818657	27454531	27454611
ENSE00000818659	27453114	27453160
ENSE00000818660	27451043	27451078
ENSE00000818661	27450749	27450895
ENSE00000818662	27445794	27445919
ENSE00000818663	27444206	27444271
ENSE00000818664	27442875	27442983
ENSE00000818665	27440237	27440441
ENSE00000818666	27439309	27439398
ENSE00000818667	27439031	27439131
ENSE00000818668	27437765	27437880
ENSE00000818669	27437396	27437496
ENSE00000818670	27437122	27437206
ENSE00000818671	27436251	27436348
ENSE00000818672	27435743	27435793
ENSE00000818673	27434513	27434559
ENSE00000818676	27432260	27432361
ENSE00000818677	27431398	27431472
ENSE00000818678	27430876	27431016
ENSE00000818681	27422304	27422383
ENSE00000818682	27420657	27420744
ENSE00000818683	27419895	27420073
ENSE00000818684	27397548	27397788
ENSE00001041766	27451485	27451509
ENSE00001412532	27458294	27459386
ENSE00001725312	27325552	27325681
ENSE00003514740	27454154	27454291
ENSE00003533663	27433435	27433552
ENSE00003589131	27430364	27430418
ENSE00003618056	27434093	27434132
ENSE00003625154	27430093	27430155

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 98.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.9312 / max 550.3680, expressed in 1569 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88133	23.2701	1165
88134	5.7155	765
88139	3.0560	290
88129	1.0100	560
205136	0.7241	402
88135	0.4094	176
88130	0.2454	105
88132	0.2344	150
88136	0.1507	87
88140	0.1156	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.80	gold quality
cerebellar hemisphere	UBERON:0002245	98.77	gold quality
cerebellar cortex	UBERON:0002129	98.74	gold quality
granulocyte	CL:0000094	98.28	gold quality
cerebellum	UBERON:0002037	98.00	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.72	gold quality
right frontal lobe	UBERON:0002810	97.49	gold quality
paraflocculus	UBERON:0005351	97.37	gold quality
monocyte	CL:0000576	97.12	gold quality
leukocyte	CL:0000738	96.83	gold quality
mononuclear cell	CL:0000842	96.77	gold quality
spleen	UBERON:0002106	96.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.12	gold quality
bone marrow cell	CL:0002092	95.92	gold quality
lymph node	UBERON:0000029	95.67	gold quality
anterior cingulate cortex	UBERON:0009835	95.67	gold quality
cingulate cortex	UBERON:0003027	95.62	gold quality
frontal pole	UBERON:0002795	95.61	gold quality
prefrontal cortex	UBERON:0000451	95.36	gold quality
blood	UBERON:0000178	95.16	gold quality
frontal cortex	UBERON:0001870	94.88	gold quality
vermiform appendix	UBERON:0001154	94.66	gold quality
skin of abdomen	UBERON:0001416	94.60	gold quality
nucleus accumbens	UBERON:0001882	94.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.33	gold quality
neocortex	UBERON:0001950	94.20	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.89	gold quality
skin of leg	UBERON:0001511	93.65	gold quality
cerebellar vermis	UBERON:0004720	93.61	gold quality
Ammon’s horn	UBERON:0001954	93.29	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8060	yes	445.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPB, CEBPG, IRF6, MYC, NR4A3, SP1, TAL1, TXK, VDR

miRNA regulators (miRDB)

66 targeting PTK2B, 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-5692A	100.00	74.40	6850
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3912-5P	99.95	66.11	925
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-5584-5P	99.49	68.22	2814

Literature-anchored findings (GeneRIF, showing 40)

• Glomerular crescents strongly expressed cell adhesion kinase beta. (PMID:11774117)
• Human umbilical vein endothelial cells express mRNA transcripts for both the full length isoform Pyk2 and the truncated isoform Pyk2-H containing the C-terminal deletion. (PMID:11820787)
• Suppressees androgen receptor transactivation vir interaction and phosphorylation of ARA44 coregulator (PMID:11856738)
• Pyk2 role in platelet activation by vWF in the early signal transduction events activated by ligand binding to glycoprotein Ib-IX-V. (PMID:11916084)
• Transforming growth factor-beta 2 is a transcriptional target via forkhead transcription factor (PMID:12011061)
• By rapidly translocating to the vicinity of the immune synapse after T cell receptor stimulation, Pyk2 plays an essential role in T cell activation and polarized secretion of cytokines. (PMID:12077257)
• This protein binds to periplakin. (PMID:12244133)
• role in negative regulation of mixed lineage kinase 3 results in cell survival (PMID:12458207)
• Critical role of the carboxyl terminus of proline-rich tyrosine kinase (Pyk2) in the activation of human neutrophils by tumor necrosis factor: separation of signals for the respiratory burst and degranulation. (PMID:12515814)
• results indicate that signaling via protein kinase B to forkhead transcription factor FKHR can account for the effect of insulin to regulate peroxisome proliferator-activated receptor-gamma coactivator-1 promoter activity via the insulin response sequence (PMID:12606503)
• PYK2 regulates transendothelial migration of cultured NK cells in response to chemokines by controlling the activation of the small GTP binding protein Rac, and thus acts as an integration point between integrin and chemokine receptor stimulation. (PMID:12626562)
• Augmented activation of Pyk2 is an immediate signaling event required for the trans-regulation of integrin alpha L beta 2 by alpha 4 beta 1 in Jurkat T cells. (PMID:12794117)
• RAFTK is activated by VEGF in human brain microvascular endothelial cells (PMID:12844492)
• PKB is an essential component of the FSH-mediated granulosa cell differentiation and that both PKB and G(s)alpha signaling pathways are required. (PMID:12933673)
• results indicate that activation of PKC is responsible for GnRH-induced phosphorylation of both ERK1/2 and Pyk2, and that Pyk2 activation does not contribute to GnRH signaling (PMID:12943720)
• A novel regulatory network RAFTK/Pyk2, Src and p38 appears to be critical for VEGF-induced endothelial cell migration. (PMID:14676843)
• Calcium signaling in ovarian surface epithelial cells not only induces telomerase activity via JNK but also activates Pyk2. (PMID:14729602)
• identified a BCR/ABL-dependent increase in expression of multiple genes involved in pre-mRNA splicing; alternative splicing of gene PYK2 resulted in increased expression of full-length Pyk2 in BCR/ABL-containing cells (PMID:14961028)
• Pyk2 facilitates EGFR- and c-Src-mediated Stat3 activation and has a role in triggering Stat3-induced oncogenesis (PMID:14963038)
• In P-selectin-activated PMNs, PYK-2 (proline-rich tyrosine kinase-2) undergoes tyrosine phosphorylation in a b2-integrin- and SRC-dependent manner, suggesting that this focal adhesion kinase may be a downstream mediator of the effect of SRC kinases. (PMID:14969582)
• PYK2 gene products mediate integrin-induced signals that regulate myelopoiesis. (PMID:15050747)
• Pyk2 signaling differentially regulates cell migration and proliferation pathways. (PMID:15070849)
• Pyk2 is a novel effector of fibroblast growth factor receptor 3 activation (PMID:15105428)
• modulation and phosphorylation of BK(Ca) channels by Pyk2 and a Src-family kinase may reflect a general cellular mechanism by which G protein-coupled receptor and/or integrin activation leads to the regulation of membrane ion channels (PMID:15128501)
• Recruitment of PYK2 to lipid rafts mediates signals important for actin reorganization in growing neurites. (PMID:15128873)
• EGFR, PYK2, Yes, and SHP-2 are involved in transduction of the TF/FVIIa signal possibly via transactivation of the EGF receptor. (PMID:15213840)
• Tyrosine phosphorylation of PYK2 mediates heregulin-induced glioma invasion (PMID:15499613)
• Activation of PI3K following beta1-integrin engagement on human CD34+ cells results in subsequent phosphorylation of PYK2, and is required for the recruitment of the PI3K/PYK2 complex to beta1-integrins at the cell surface. (PMID:15539082)
• proline-rich tyrosine kinase 2 (PYK2) is phosphorylated on tyrosine residues 402 and 580 induced by ephrin-A1 (PMID:15585656)
• Pyk2 is a phosphorylated beta(3) binding partner, providing a potential structural and signaling platform to achieve alpha(V)beta(3) -mediated remodeling of the actin cytoskele (PMID:15695828)
• Pyk2 has a role in the reduced cell-cell adhesion induced by the Rac-mediated production of ROS through the tyrosine phosphorylation of beta-catenin (PMID:15778498)
• bFGF significantly stimulated PKB activity in CNE- I nasopharyngeal carcinoma cell line. (PMID:15835820)
• Pyk2 is a critical regulatory component and a molecular switch to overcome the suppression of neutrophil oxidant generation by cell adhesion. (PMID:15944312)
• Pyk2 plays a central role in the migratory behavior of glioblastomas (PMID:15967096)
• Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway (PMID:16055703)
• Pyk2 may mediate a signal necessary for beta2 integrin function in PMN tethered by E-selectin. (PMID:16433632)
• The tyrosine kinase Pyk2 was highly phosphorylated upon induction of cell polarity but not during cell spreading (PMID:16514607)
• Vascular endothelial growth factor (VEGF) elicits the activation of the VEGFR2-ROCK pathway, leading to phosphorylation of Ser732 within FAK which changes the conformation of FAK, making it accessible to Pyk2. (PMID:16760434)
• PYK2 mediates anti-apoptotic AKT signaling in response to benzo[a]pyrene diol epoxide in mammary epithelial cells (PMID:16774943)
• Our data indicate that Pyk2 plays a central role in the mechanism that regulate cell-cell and cell-substrate interaction and lack of its kinase activity induces prostate cells to acquire a malignant, migrating phenotype. (PMID:16783820)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptk2bb	ENSDARG00000039577
mus_musculus	Ptk2b	ENSMUSG00000059456
rattus_norvegicus	Ptk2b	ENSRNOG00000027839

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ITK (ENSG00000113263), ZAP70 (ENSG00000115085), 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

Protein-tyrosine kinase 2-beta — Q14289 (reviewed: Q14289)

Alternative names: Calcium-dependent tyrosine kinase, Calcium-regulated non-receptor proline-rich tyrosine kinase, Cell adhesion kinase beta, Focal adhesion kinase 2, Proline-rich tyrosine kinase 2, Related adhesion focal tyrosine kinase

All UniProt accessions (6): C9JHV9, E5RHL2, E5RJ77, E5RK84, Q14289, H0YB74

UniProt curated annotations — full annotation on UniProt →

Function. Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at ‘Tyr-9, ‘Tyr-373’, and ‘Tyr-376’. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2.

Subunit / interactions. Homodimer, or homooligomer. Interacts with SIRPA and SH2D3C. Interacts with ARHGAP10. Interacts with DLG4. Interacts with KCNA2. Interacts with NPHP1, ASAP1, ASAP2, ARHGAP26, SKAP2 and TGFB1I1. The Tyr-402 phosphorylated form interacts with SRC (via SH2 domain) and SRC family members. Forms a signaling complex with EPHA1, LCK and phosphatidylinositol 3-kinase; upon activation by EFNA1. Interacts with GRB2 (via SH2 domain). Interacts with P53/TP53 and MDM2. Interacts with MYLK. Interacts with BCAR1. Interacts with PDPK1. Interacts (hypophosphorylated) with PXN. Interacts with RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with LPXN and PTPN12.

Subcellular location. Cytoplasm. Perinuclear region. Cell membrane. Cell junction. Focal adhesion. Cell projection. Lamellipodium. Cell cortex. Nucleus.

Tissue specificity. Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes.

Post-translational modifications. Phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration; this activation is indirect and may be mediated by production of reactive oxygen species (ROS). Tyr-402 is the major autophosphorylation site, but other kinases can also phosphorylate Tyr-402. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-402 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-579; Tyr-580 and Tyr-881. Phosphorylation at Tyr-881 is important for interaction with GRB2. Phosphorylated on tyrosine residues upon activation of FGR and PKC. Recruitment by NPHP1 to cell matrix adhesions initiates Tyr-402 phosphorylation. In monocytes, adherence to substrata is required for tyrosine phosphorylation and kinase activation. Angiotensin II, thapsigargin and L-alpha-lysophosphatidic acid (LPA) also induce autophosphorylation and increase kinase activity. Phosphorylation by MYLK promotes ITGB2 activation and is thus essential to trigger neutrophil transmigration during lung injury. Dephosphorylated by PTPN12.

Disease relevance. Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.

Activity regulation. Activated in response to stimuli that lead to increased intracellular Ca(2+) levels; this activation is indirect and may be mediated by calcium-mediated production of reactive oxygen species (ROS). Activated by autophosphorylation at Tyr-402; this creates a binding site for SRC family kinases and leads to phosphorylation at additional tyrosine residues. Phosphorylation at Tyr-402, Tyr-579 and Tyr-580 is required for optimal kinase activity. Inhibited by PF-562,271, BIRB796, PF-4618433 and by PF-431396, PF-2318841 and their derivatives. Inhibited by sulfoximine-substituted trifluoromethylpyrimidines. Inhibited by 4-amino and 5-aryl substituted pyridinone compounds.

Miscellaneous. Promotes bone resorption, and thus PTK2B/PYK2 inhibitors might be used to treat osteoporosis.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q14289-1	1	yes
Q14289-2	2, PYK2H

RefSeq proteins (4): NP_004094, NP_775266, NP_775267, NP_775268* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR005189	Focal_adhesion_kin_target_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR020635	Tyr_kinase_cat_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily
IPR036137	Focal_adhe_kin_target_dom_sf	Homologous_superfamily
IPR041390	FADK_N	Domain
IPR041784	FAK1/PYK2_FERM_C	Domain
IPR049385	FAK1-like_FERM_C	Domain

Pfam: PF00373, PF03623, PF07714, PF18038, PF21477

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), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (116 total): helix 38, strand 25, modified residue 16, turn 10, sequence variant 5, sequence conflict 5, mutagenesis site 4, domain 3, binding site 3, region of interest 3, chain 1, splice variant 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
3CC6	X-RAY DIFFRACTION	1.6
3FZS	X-RAY DIFFRACTION	1.75
4XEK	X-RAY DIFFRACTION	1.79
8XOX	X-RAY DIFFRACTION	1.9
3FZT	X-RAY DIFFRACTION	1.95
5TO8	X-RAY DIFFRACTION	1.98
4H1M	X-RAY DIFFRACTION	1.99
3H3C	X-RAY DIFFRACTION	2
4H1J	X-RAY DIFFRACTION	2
8YGX	X-RAY DIFFRACTION	2
4XEV	X-RAY DIFFRACTION	2.01
3FZP	X-RAY DIFFRACTION	2.1
5TOB	X-RAY DIFFRACTION	2.12
3FZO	X-RAY DIFFRACTION	2.2
4XEF	X-RAY DIFFRACTION	2.5
3GM3	X-RAY DIFFRACTION	2.6
3ET7	X-RAY DIFFRACTION	2.7
3FZR	X-RAY DIFFRACTION	2.7
3GM2	X-RAY DIFFRACTION	2.71
3GM1	X-RAY DIFFRACTION	2.95
3U3F	X-RAY DIFFRACTION	3.1
6LF3	X-RAY DIFFRACTION	3.2
4EKU	X-RAY DIFFRACTION	3.25
4R32	X-RAY DIFFRACTION	3.5
2LK4	SOLUTION NMR
7PLL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14289-F1	76.47	0.42

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): 549 (proton acceptor)

Ligand- & substrate-binding residues (3): 457; 503–509; 431–439

Post-translational modifications (16): 361, 375, 399, 402, 579, 580, 722, 762, 765, 819, 834, 839, 842, 849, 866, 881

Mutagenesis-validated functional residues (4):

Position	Phenotype
402	abolishes autophosphorylation. abolishes interaction with src.
457	abolishes kinase activity.
859	loss of interaction with nphp1.
881	loss of phosphorylation site. strongly reduced interaction with grb2.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-391160	Signal regulatory protein family interactions
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9020558	Interleukin-2 signaling

MSigDB gene sets: 685 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_POTASSIUM_ION_TRANSPORT, RNGTGGGC_UNKNOWN, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, MODY_HIPPOCAMPUS_POSTNATAL, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_SYNAPSE_ASSEMBLY

GO Biological Process (63): neuron migration (GO:0001764), positive regulation of cell-matrix adhesion (GO:0001954), sprouting angiogenesis (GO:0002040), adaptive immune response (GO:0002250), marginal zone B cell differentiation (GO:0002315), apoptotic process (GO:0006915), cellular defense response (GO:0006968), Golgi organization (GO:0007030), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), signal complex assembly (GO:0007172), epidermal growth factor receptor signaling pathway (GO:0007173), integrin-mediated signaling pathway (GO:0007229), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), regulation of cell shape (GO:0008360), positive regulation of endothelial cell migration (GO:0010595), regulation of macrophage chemotaxis (GO:0010758), positive regulation of neuron projection development (GO:0010976), peptidyl-tyrosine phosphorylation (GO:0018108), regulation of cell adhesion (GO:0030155), positive regulation of cell migration (GO:0030335), negative regulation of bone mineralization (GO:0030502), positive regulation of actin filament polymerization (GO:0030838), cortical cytoskeleton organization (GO:0030865), regulation of actin cytoskeleton organization (GO:0032956), tumor necrosis factor-mediated signaling pathway (GO:0033209), ionotropic glutamate receptor signaling pathway (GO:0035235), peptidyl-tyrosine autophosphorylation (GO:0038083), activation of Janus kinase activity (GO:0042976), negative regulation of apoptotic process (GO:0043066), negative regulation of potassium ion transport (GO:0043267), negative regulation of neuron apoptotic process (GO:0043524), bone resorption (GO:0045453), negative regulation of myeloid cell differentiation (GO:0045638), positive regulation of angiogenesis (GO:0045766), positive regulation of protein kinase activity (GO:0045860), positive regulation of JNK cascade (GO:0046330), protein autophosphorylation (GO:0046777), vascular endothelial growth factor receptor signaling pathway (GO:0048010)

GO Molecular Function (12): calcium/calmodulin-dependent protein kinase activity (GO:0004683), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), ATP binding (GO:0005524), signaling receptor activator activity (GO:0030546), ionotropic glutamate receptor binding (GO:0035255), neurotransmitter receptor regulator activity (GO:0099602), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (23): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell cortex (GO:0005938), postsynaptic density (GO:0014069), NMDA selective glutamate receptor complex (GO:0017146), lamellipodium (GO:0030027), dendrite (GO:0030425), growth cone (GO:0030426), neuronal cell body (GO:0043025), cell body (GO:0044297), perinuclear region of cytoplasm (GO:0048471), apical dendrite (GO:0097440), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), postsynaptic density, intracellular component (GO:0099092), cytoskeleton (GO:0005856), membrane (GO:0016020), cell junction (GO:0030054), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cell-Cell communication	1
Signaling by VEGF	1
RHO GTPase cycle	1
Interleukin-2 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
cell population proliferation	2
regulation of cell population proliferation	2
signaling receptor regulator activity	2
cell periphery	2
synapse	2
cell migration	1
generation of neurons	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
angiogenesis	1
immune response	1
mature B cell differentiation involved in immune response	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	1
organelle organization	1
endomembrane system organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
regulation of signal transduction	1
protein-containing complex assembly	1
ERBB signaling pathway	1
cell surface receptor signaling pathway	1
positive regulation of cellular process	1
negative regulation of cellular process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
regulation of leukocyte chemotaxis	1
macrophage chemotaxis	1

Protein interactions and networks

STRING

2758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTK2B	PXN	P49023	997
PTK2B	SRC	P12931	987
PTK2B	RB1CC1	Q8TDY2	969
PTK2B	BCAR1	P56945	951
PTK2B	TGFB1I1	O43294	930
PTK2B	VCL	P18206	925
PTK2B	PITPNM1	O00562	922
PTK2B	LPXN	O60711	901
PTK2B	NPHP4	O75161	869
PTK2B	GRB2	P29354	866
PTK2B	LYN	P07948	854
PTK2B	PTK2	Q05397	842
PTK2B	PITPNM3	Q9BZ71	838
PTK2B	CBL	P22681	835
PTK2B	PTPN12	Q05209	831

IntAct

84 interactions, top by confidence:

A	B	Type	Score
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
FYN	PTK2B	psi-mi:“MI:0914”(association)	0.700
SRC	PTK2B	psi-mi:“MI:0914”(association)	0.640
RHOU	PTK2B	psi-mi:“MI:0915”(physical association)	0.580
PTK2B	RHOU	psi-mi:“MI:0915”(physical association)	0.580
APP	PTK2B	psi-mi:“MI:0915”(physical association)	0.560
PTK2B	TGFB1I1	psi-mi:“MI:0914”(association)	0.530
STAT3	PTK2B	psi-mi:“MI:0915”(physical association)	0.530
STAT3	PTK2B	psi-mi:“MI:0403”(colocalization)	0.530
PTK2B	STAT3	psi-mi:“MI:0915”(physical association)	0.530
EGFR	XPOT	psi-mi:“MI:0914”(association)	0.530
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460
PTK2B	MAP3K4	psi-mi:“MI:0403”(colocalization)	0.460
PTK2B	MAP3K4	psi-mi:“MI:0915”(physical association)	0.460
MATK	PTK2B	psi-mi:“MI:0914”(association)	0.460
PTK2B	ITGB1	psi-mi:“MI:0914”(association)	0.430
PTK2B	ITGAV	psi-mi:“MI:0403”(colocalization)	0.430
PTK2B	ITGB1	psi-mi:“MI:0403”(colocalization)	0.430

BioGRID (161): ERBB2 (Co-localization), PTK2B (Two-hybrid), PTK2B (Two-hybrid), PTK2B (Affinity Capture-Western), PTK2B (Affinity Capture-Western), PTK2B (Affinity Capture-Western), TGFB1I1 (Reconstituted Complex), TGFB1I1 (Two-hybrid), TGFB1I1 (Affinity Capture-Western), CBL (Affinity Capture-Western), PTK2B (Affinity Capture-Western), PTK2B (Affinity Capture-Western), PTK2B (Reconstituted Complex), PTK2B (Affinity Capture-RNA), PTK2B (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2K344, D3ZGS3, F1M386, F1MSG6, F1PBJ0, G5EF51, O00329, O02697, O35242, O35904, O70481, O88763, O94830, P32871, P42336, P42337, P42338, P42339, P42347, P42348, P48736, P50520, P54676, P70600, Q01968, Q14289, Q14BI7, Q16JS8, Q3MHU3, Q3UYK3, Q4KWH5, Q4KWH8, Q5D891, Q5ZI89, Q6AZN6, Q6GQ76, Q6NVF0, Q6PF93, Q7Z392, Q80Y98

Diamond homologs: F1N9Y5, F1RDG9, G5EBZ8, G5EE56, O02466, O18735, O45539, O54967, P00519, P00520, P00521, P00522, P00525, P00526, P00528, P00533, P00534, P00535, P03949, P04412, P04626, P06239, P06240, P06494, P07948, P08103, P08630, P08631, P0CY46, P10447, P11273, P15209, P17713, P24786, P25911, P27446, P29317, P42679, P42680, P42681

SIGNOR signaling

31 interactions.

A	Effect	B	Mechanism
PTPN12	“down-regulates activity”	PTK2B	dephosphorylation
PTK2B	up-regulates	PTK2B	phosphorylation
SRC	up-regulates	PTK2B	phosphorylation
PTK2B	up-regulates	PTK2	phosphorylation
PTK2B	down-regulates	NOS3	phosphorylation
N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide	down-regulates	PTK2B	“chemical inhibition”
PTK2B	“up-regulates activity”	STAP1	phosphorylation
PTK2B	“down-regulates activity”	ASAP1	phosphorylation
PTK2B	“up-regulates activity”	ASAP2	phosphorylation
PTPN11	“down-regulates activity”	PTK2B	dephosphorylation
PTK2B	“up-regulates activity”	TBK1	phosphorylation
PTK2B	“up-regulates activity”	NPHP1	phosphorylation
PTK2B	“down-regulates activity”	GSN	phosphorylation
PTK2B	“up-regulates activity”	CTTN	phosphorylation
PTK2B	“up-regulates quantity”	ID3	phosphorylation
PTK2B	“down-regulates quantity by destabilization”	PXN	phosphorylation
PTK2B	“up-regulates activity”	STAT3	phosphorylation
MET	“up-regulates activity”	PTK2B	phosphorylation
PTK2B	“up-regulates activity”	BCAR1	phosphorylation
PTK2B	“up-regulates activity”	LSR	phosphorylation
PTPN6	down-regulates	PTK2B	dephosphorylation
PTK2B	unknown	SNCA	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 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
Signaling by ERBB2	6	50.6×	9e-07
RHOU GTPase cycle	5	34.0×	8e-05
VEGFA-VEGFR2 Pathway	5	17.0×	5e-04
Constitutive Signaling by Aberrant PI3K in Cancer	5	15.5×	6e-04
RAC2 GTPase cycle	5	15.5×	6e-04
RAC3 GTPase cycle	5	14.5×	6e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	14.2×	2e-04
PIP3 activates AKT signaling	7	11.4×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
substrate adhesion-dependent cell spreading	5	33.7×	8e-05
epidermal growth factor receptor signaling pathway	6	29.2×	2e-05
cell-cell adhesion	7	13.9×	1e-04
intracellular signal transduction	11	8.2×	2e-05
positive regulation of cell migration	6	7.3×	8e-03
cell migration	6	7.2×	8e-03
cell adhesion	9	6.6×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	131
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

5690 predictions. Top by Δscore:

Variant	Effect	Δscore
8:27311705:GCACC:G	donor_gain	1.0000
8:27397787:GG:G	donor_gain	1.0000
8:27397788:GG:G	donor_gain	1.0000
8:27397788:GGTA:G	donor_loss	1.0000
8:27397789:G:GG	donor_gain	1.0000
8:27397789:GTAA:G	donor_loss	1.0000
8:27397790:T:G	donor_loss	1.0000
8:27419890:T:TA	acceptor_gain	1.0000
8:27419892:CAGG:C	acceptor_gain	1.0000
8:27419893:A:AG	acceptor_gain	1.0000
8:27419893:AG:A	acceptor_gain	1.0000
8:27419893:AGGA:A	acceptor_gain	1.0000
8:27419894:G:GC	acceptor_gain	1.0000
8:27419894:GG:G	acceptor_gain	1.0000
8:27419894:GGA:G	acceptor_gain	1.0000
8:27419894:GGAG:G	acceptor_gain	1.0000
8:27419894:GGAGA:G	acceptor_gain	1.0000
8:27420653:GCAG:G	acceptor_loss	1.0000
8:27420654:CAGGT:C	acceptor_loss	1.0000
8:27420655:A:AT	acceptor_loss	1.0000
8:27420656:G:GT	acceptor_loss	1.0000
8:27420656:GGT:G	acceptor_gain	1.0000
8:27420656:GGTA:G	acceptor_gain	1.0000
8:27420656:GGTAT:G	acceptor_gain	1.0000
8:27420742:CAG:C	donor_loss	1.0000
8:27420743:AG:A	donor_loss	1.0000
8:27420744:GG:G	donor_loss	1.0000
8:27420745:G:A	donor_loss	1.0000
8:27420746:T:G	donor_loss	1.0000
8:27422299:A:AG	acceptor_gain	1.0000

AlphaMissense

6660 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:27419971:T:C	L94P	1.000
8:27420069:T:A	W127R	1.000
8:27420069:T:C	W127R	1.000
8:27420665:T:C	L131P	1.000
8:27422359:T:C	L176P	1.000
8:27422365:T:C	L178P	1.000
8:27422367:G:C	G179R	1.000
8:27422368:G:A	G179D	1.000
8:27422370:T:C	C180R	1.000
8:27422372:C:G	C180W	1.000
8:27422374:T:C	L181P	1.000
8:27422380:T:C	L183P	1.000
8:27430387:T:C	F213S	1.000
8:27430390:T:C	F214S	1.000
8:27431423:T:C	L279P	1.000
8:27433487:T:C	L347P	1.000
8:27437147:T:A	V456D	1.000
8:27437151:G:C	K457N	1.000
8:27437151:G:T	K457N	1.000
8:27437880:G:T	R548M	1.000
8:27439033:A:C	D549A	1.000
8:27439033:A:T	D549V	1.000
8:27439087:A:C	D567A	1.000
8:27439087:A:T	D567V	1.000
8:27439332:A:G	K590E	1.000
8:27439334:A:C	K590N	1.000
8:27439334:A:T	K590N	1.000
8:27439335:T:A	W591R	1.000
8:27439335:T:C	W591R	1.000
8:27439337:G:C	W591C	1.000

dbSNP variants (sampled 300 via entrez): RS1000034225 (8:27376646 C>G), RS1000105590 (8:27449511 T>C), RS1000135689 (8:27311637 C>A), RS1000145999 (8:27402940 AG>A), RS1000147631 (8:27367961 C>T), RS1000162015 (8:27347042 G>T), RS1000194467 (8:27342839 A>G), RS1000216274 (8:27454885 C>G), RS1000243306 (8:27436863 C>T), RS1000251947 (8:27381124 CTG>C), RS1000259881 (8:27408146 A>G), RS1000269424 (8:27341119 T>C,G), RS1000300015 (8:27413787 T>G), RS1000325879 (8:27420260 T>C), RS1000330005 (8:27362477 G>A)

Disease associations

OMIM: gene MIM:601212 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST001786_19	Dental caries	4.000000e-07
GCST002245_19	Alzheimer’s disease (late onset)	7.000000e-14
GCST002817_16	Alzheimer’s disease in APOE e4- carriers	8.000000e-06
GCST003043_91	Inflammatory bowel disease	6.000000e-08
GCST003044_18	Crohn’s disease	2.000000e-06
GCST004521_193	Autism spectrum disorder or schizophrenia	3.000000e-09
GCST006575_16	Takayasu arteritis	6.000000e-06
GCST006575_58	Takayasu arteritis	9.000000e-06
GCST006803_90	Schizophrenia	8.000000e-12
GCST006984_3	Takayasu arteritis	3.000000e-13
GCST007319_20	Alzheimer’s disease (late onset)	7.000000e-08
GCST007319_7	Alzheimer’s disease (late onset)	6.000000e-20
GCST007320_104	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-11
GCST007320_4	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-19
GCST007321_10	Family history of Alzheimer’s disease	2.000000e-07
GCST007321_19	Family history of Alzheimer’s disease	7.000000e-09
GCST009021_14	Alzheimer’s disease	6.000000e-09
GCST009377_3	Bone mineral density	7.000000e-08
GCST009378_12	Bone mineral content	2.000000e-07
GCST009378_17	Bone mineral content	9.000000e-07
GCST009378_2	Bone mineral content	5.000000e-06
GCST009378_25	Bone mineral content	1.000000e-06
GCST010988_290	Adult body size	1.000000e-10
GCST011938_1	Takayasu arteritis	2.000000e-06
GCST011939_3	Takayasu arteritis	1.000000e-09
GCST90002381_369	Eosinophil count	4.000000e-11
GCST90002382_171	Eosinophil percentage of white cells	9.000000e-10
GCST90002393_566	Monocyte count	1.000000e-13
GCST90002407_501	White blood cell count	2.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0009268	family history of Alzheimer’s disease
EFO:0007620	volumetric bone mineral density
EFO:0007621	bone mineral content measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5469 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

43 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 200,777 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3286830	LORLATINIB	4	3,598
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1231124	AZD-1480	2	1,576
CHEMBL1721885	SU-014813	2	363
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL1967878	CENISERTIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL3039525	GOLVATINIB	2
CHEMBL3991932	PEXMETINIB	2
CHEMBL402548	DANUSERTIB	2
CHEMBL475251	R-406	2
CHEMBL513909	BI-2536	2
CHEMBL572878	TOZASERTIB	2
CHEMBL574737	UCN-01	2
CHEMBL575448	BMS-754807	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Fak family

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
NVP-TAE 226	Inhibition	8.7	pIC50
PF-562271	Inhibition	7.89	pIC50
conteltinib	Inhibition	7.7	pIC50
aloisine	Inhibition	6.03	pKi

Binding affinities (BindingDB)

248 measured of 463 human assays (472 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[3-[[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]methanone	KI	0.165 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	0.181 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
[3-[[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]methanone	KI	0.376 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]methanone	KI	0.683 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	0.912 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
5-{[(8S)-6,8-dimethyl-6,9-diazaspiro[4.5]dec-9-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine	KI	1.01 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N-(2-ethoxy-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine	KI	1.12 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(3-fluoro-6-methyl-2-pyridinyl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperidin-1-yl]methanone	KI	1.17 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(2-ethyl-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]methanone	KI	1.64 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
Staurosporine	KD	1.7 nM
(4-fluoro-1-methylpiperidin-4-yl)-[3-[[5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]methanone	KI	1.71 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N-(5-fluoro-2-propylpyrimidin-4-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine	KI	1.73 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[2-(ethylamino)-5-fluoropyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]methanone	KI	2.03 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N-[5-fluoro-2-(methoxymethyl)pyrimidin-4-yl]-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethyl piperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine	KI	2.1 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(6-ethoxy-3-fluoro-2-pyridinyl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]-[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl]methanone	KI	2.11 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
4-[[6,6-dimethyl-5-[(2S,5R)-2,4,5-trimethylpiperazine-1-carbonyl]-1,4-dihydropyrrolo[3,4-d]pyrazol-3-yl]amino]pyrimidine-2-carbonitrile	KI	2.43 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(3-fluoro-6-methyl-2-pyridinyl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]-[(2S,5S)-2,4,5-trimethylpiperidin-1-yl]methanone	KI	2.63 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N4-(6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-N2-ethyl-5-fluoropyrimidine-2,4-diamine	KI	2.69 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-4-(2-methoxyethyl)-2,5-dimethylpiperazin-1-yl]methanone	KI	3.33 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[2-(ethylamino)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	3.39 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(5-fluoro-2-propan-2-ylpyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	3.67 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[5-fluoro-2-(propan-2-ylamino)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	3.81 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[2-(cyclopropylamino)-5-fluoropyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	3.95 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N-(4-ethoxypyrimidin-2-yl)-6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine	KI	4.24 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N2-ethyl-5-fluoro-N4-(5-{[(2S,5R)-4-(3-methoxypropyl)-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)pyrimidine-2,4-diamine acetate salt	KI	5.09 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N-(2-ethyl-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5-{[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine	KI	5.43 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(3S,8aS)-3-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-[3-[(3-fluoro-6-methyl-2-pyridinyl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]methanone	KI	6.43 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(5-fluoro-2-methylpyrimidin-4-yl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	7.21 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(3S,8aS)-3,8a-dimethyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-[3-[(3-fluoro-6-methyl-2-pyridinyl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]methanone	KI	8.64 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[2-(dimethylamino)-5-fluoropyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	8.75 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[2-(dimethylamino)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	9.73 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N-(2-ethyl-5-fluoropyrimidin-4-yl)-6,6-dimethyl-5-{[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine acetate salt	KI	10.5 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[5-fluoro-2-(methylamino)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	10.8 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(2S,5R)-2,5-dimethyl-4-(oxan-4-ylmethyl)piperazin-1-yl]-[3-[(4,6-dimethylpyrimidin-2-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]methanone	KI	11.1 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(3S,8aS)-3,8a-dimethyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-[3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]methanone	KI	11.2 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[5-fluoro-2-(3-hydroxypropoxy)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	12.8 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(2-ethoxypyrimidin-4-yl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]-[(2S,5S)-2,4,5-trimethylpiperidin-1-yl]methanone	KI	13.1 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[2-(ethylamino)-5-fluoropyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-4-(2-methoxyethyl)-2,5-dimethylpiperazin-1-yl]methanone	KI	13.5 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl]-[3-[(5-fluoro-2,6-dimethylpyrimidin-4-yl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]methanone	KI	14.8 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(2S,5R)-2,5-dimethyl-4-(oxan-4-ylmethyl)piperazin-1-yl]-[3-[(5-fluoro-2-methylpyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]methanone	KI	14.9 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[5-fluoro-2-(2-methoxyethoxy)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S,5R)-2,4,5-trimethylpiperazin-1-yl]methanone	KI	15.2 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-4-[(4-hydroxyoxan-4-yl)methyl]-2-methylpiperazin-1-yl]methanone	KI	15.3 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[5-fluoro-2-(methoxymethyl)pyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-5-(2-hydroxyethyl)-2,4-dimethylpiperazin-1-yl]methanone	KI	15.6 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[(4-ethoxypyrimidin-2-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2R,5R)-1-(3-methoxypropyl)-2,5-dimethylpiperidin-4-yl]methanone	KI	16.1 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
N-(2-ethoxy-5-fluoropyrimidin-4-yl)-5-[(4-fluoro-1-methylpiperidin-4-yl)carbonyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine	KI	16.8 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[3-[[2-(cyclopropylmethylamino)-5-fluoropyrimidin-4-yl]amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]-[(2S)-2,4,5,5-tetramethylpiperazin-1-yl]methanone	KI	17.9 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(2S,5R)-2,5-dimethylpiperazin-1-yl]-[3-[(5-fluoro-2-methylpyrimidin-4-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]methanone	KI	18.1 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl]-[3-[(5-fluoro-2-methylpyrimidin-4-yl)amino]-6,6-dimethyl-1,2,3,3a,4,6a-hexahydropyrrolo[3,4-c]pyrazol-5-yl]methanone	KI	18.9 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors
[(2S,5R)-2,5-dimethyl-4-(oxan-4-ylmethyl)piperazin-1-yl]-[3-[(4-methoxypyrimidin-2-yl)amino]-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazol-5-yl]methanone	KI	19.2 nM	US-9518060: Substituted pyrrolo[3,4-c]pyrazoles as PKC kinase inhibitors

ChEMBL bioactivities

420 potent at pChembl≥5 of 465 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	DEFACTINIB
9.22	IC50	0.6	nM	CHEMBL4862042
9.22	IC50	0.6	nM	DEFACTINIB
9.17	IC50	0.67	nM	CHEMBL3949755
9.08	IC50	0.84	nM	CHEMBL3958414
9.05	IC50	0.9	nM	CHEMBL3956954
8.96	Kd	1.1	nM	TAE-684
8.88	IC50	1.31	nM	CHEMBL3987106
8.85	IC50	1.4	nM	PF-00562271
8.82	IC50	1.5	nM	CHEMBL3899046
8.81	IC50	1.55	nM	CHEMBL3969464
8.80	Ki	1.585	nM	CHEMBL1971029
8.72	IC50	1.9	nM	CHEMBL3908093
8.70	IC50	2	nM	CHEMBL452341
8.62	IC50	2.4	nM	CONTELTINIB
8.59	IC50	2.6	nM	CHEMBL3961368
8.57	IC50	2.7	nM	CHEMBL3977870
8.51	IC50	3.1	nM	CHEMBL3889951
8.50	Ki	3.162	nM	PF-00562271
8.46	IC50	3.5	nM	CHEMBL3912281
8.46	Kd	3.5	nM	STAUROSPORINE
8.30	IC50	5	nM	CHEMBL487229
8.24	Kd	5.7	nM	PF-00562271
8.22	IC50	6	nM	CHEMBL455680
8.19	IC50	6.4	nM	CHEMBL2207440
8.16	Kd	6.9	nM	CHEMBL472212
8.10	Ki	7.943	nM	CHEMBL1241473
8.07	IC50	8.44	nM	STAUROSPORINE
8.05	IC50	8.81	nM	STAUROSPORINE
8.00	Kd	10	nM	HESPERADIN
8.00	IC50	10	nM	CHEMBL2029181
8.00	Ki	10	nM	CHEMBL1987034
7.98	Ki	10.47	nM	CHEMBL261641
7.97	IC50	10.6	nM	STAUROSPORINE
7.96	IC50	11	nM	CHEMBL472212
7.92	IC50	12	nM	CHEMBL3128069
7.90	IC50	12.5	nM	CHEMBL2207441
7.89	IC50	13	nM	PF-00562271
7.85	IC50	14	nM	CHEMBL2430359
7.85	IC50	14	nM	LORLATINIB
7.85	Ki	14	nM	LORLATINIB
7.85	IC50	14	nM	CHEMBL5712062
7.85	IC50	14	nM	PF-00562271
7.85	Kd	14	nM	FORETINIB
7.82	IC50	15	nM	CHEMBL488089
7.80	IC50	16	nM	CHEMBL2029181
7.77	IC50	17	nM	CHEMBL529889
7.77	IC50	16.95	nM	CHEMBL458997
7.71	IC50	19.5	nM	CHEMBL3965256
7.70	Ki	19.95	nM	CHEMBL411903

PubChem BioAssay actives

248 with measured affinity, of 1334 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-methyl-4-[[4-[[2-[methyl(methylsulfonyl)amino]-3-pyridinyl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	1755642: Inhibition of human pyk2	ic50	0.0006	uM
16-methylsulfonyl-6-(trifluoromethyl)-2,4,8,14,16,25-hexazatetracyclo[18.3.1.13,7.010,15]pentacosa-1(23),3,5,7(25),10(15),11,13,20(24),21-nonaene	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0007	uM
4-[(18E)-16-methylsulfonyl-6-(trifluoromethyl)-2,4,8,14,16,25-hexazatetracyclo[18.3.1.13,7.010,15]pentacosa-1(24),3,5,7(25),10(15),11,13,18,20,22-decaen-21-yl]morpholine	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0008	uM
16-methylsulfonyl-26-(trifluoromethyl)-2,10,16,24,28,29-hexazapentacyclo[23.3.1.13,7.06,10.017,22]triaconta-1(28),3(30),4,6,17,19,21,25(29),26-nonaen-11-one	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0009	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	624732: Binding constant for PYK2 kinase domain	kd	0.0011	uM
4-[16-methylsulfonyl-6-(trifluoromethyl)-2,4,8,14,16,25-hexazatetracyclo[18.3.1.13,7.010,15]pentacosa-1(24),3,5,7(25),10(15),11,13,20,22-nonaen-21-yl]morpholine	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0013	uM
N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]-2-pyridinyl]methanesulfonamide	1755630: Inhibition of pyk2 (unknown origin)	ic50	0.0014	uM
24-methyl-16-methylsulfonyl-26-(trifluoromethyl)-2,10,16,24,28,29-hexazapentacyclo[23.3.1.13,7.06,10.017,22]triaconta-1(28),3(30),4,6,17,19,21,25(29),26-nonaen-11-one	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0015	uM
4-[(18E)-8-methyl-16-methylsulfonyl-6-(trifluoromethyl)-2,4,8,14,16,25-hexazatetracyclo[18.3.1.13,7.010,15]pentacosa-1(24),3,5,7(25),10(15),11,13,18,20,22-decaen-21-yl]morpholine	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0015	uM
16-ethylsulfonyl-26-(trifluoromethyl)-2,10,16,24,28,29-hexazapentacyclo[23.3.1.13,7.06,10.017,22]triaconta-1(28),3(30),4,6,17,19,21,25(29),26-nonaen-11-one	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0019	uM
N-[2-[[[2-[(2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]phenyl]-N-methylmethanesulfonamide	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0020	uM
(18E)-16-methylsulfonyl-6-(trifluoromethyl)-2,4,8,14,16,25-hexazatetracyclo[18.3.1.13,7.010,15]pentacosa-1(23),3,5,7(25),10(15),11,13,18,20(24),21-decaene	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0026	uM
4-[(18E)-8-methyl-16-methylsulfonyl-6-(trifluoromethyl)-2,4,8,13,16,25-hexazatetracyclo[18.3.1.13,7.010,15]pentacosa-1(24),3,5,7(25),10(15),11,13,18,20,22-decaen-21-yl]morpholine	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0027	uM
16-methylsulfonyl-26-(trifluoromethyl)-2,10,16,18,24,28,29-heptazapentacyclo[23.3.1.13,7.06,10.017,22]triaconta-1(28),3(30),4,6,17(22),18,20,25(29),26-nonaen-11-one	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0031	uM
16,16-dioxo-26-(trifluoromethyl)-16lambda6-thia-2,10,15,18,24,28,29-heptazapentacyclo[23.3.1.13,7.06,10.017,22]triaconta-1(28),3(30),4,6,17(22),18,20,25(29),26-nonaen-11-one	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0035	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	436048: Binding constant for full-length PTK2B	kd	0.0035	uM
N-methyl-N-[2-[[[2-[(1-oxo-2,3-dihydroisoindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]phenyl]methanesulfonamide	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0050	uM
1-[4-[[4-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]ethanone	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0060	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-(5-quinolin-6-yl-1H-pyrazol-3-yl)urea	717755: Inhibition of PYK2 after 2hrs by fluorescence polarization assay	ic50	0.0064	uM
N-methyl-N-[2-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]phenyl]methanesulfonamide	2200416: Binding affinity to human recombinant PYK2 (amino acids 420-691) expressed in Escherichia coli, BL21 (DE3) assessed as equilibrium dissociation constant by SPR assay	kd	0.0069	uM
N-[2-hydroxy-3-[C-phenyl-N-[4-(piperidin-1-ylmethyl)phenyl]carbonimidoyl]-1H-indol-5-yl]ethanesulfonamide	389055: Binding affinity to human PYK2	kd	0.0100	uM
4-N-[(1R,2R)-2-(dimethylamino)cyclopentyl]-2-N-[4-(N-ethyl-S-methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine	599634: Inhibition of PYK2 by PYK2-LI-COR cellular assay	ic50	0.0100	uM
(3Z)-N-(3-chlorophenyl)-3-[[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrol-2-yl]methylidene]-N-methyl-2-oxo-1H-indole-5-sulfonamide	661602: Inhibition of human recombinant PYK2 by ESI-MS analysis	ki	0.0105	uM
(2R)-2-[5-[6-amino-5-[(1R)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]-3-pyridinyl]-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol	1074701: Inhibition of PTK2B (unknown origin) using Km levels of ATP	ic50	0.0120	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-(5-quinoxalin-6-yl-1H-pyrazol-3-yl)urea	717755: Inhibition of PYK2 after 2hrs by fluorescence polarization assay	ic50	0.0125	uM
(16R)-19-amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetrazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,11,13,18,20-heptaene-3-carbonitrile	2187700: Inhibition of GST-tagged recombinant full length PTK2B (unknown origin) expressed in Insect cell	ic50	0.0140	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624732: Binding constant for PYK2 kinase domain	kd	0.0140	uM
Lorlatinib	1153113: Inhibition of PTK2B (unknown origin) by TR-FRET-based Z’-LYTE assay	ic50	0.0140	uM
5-[[4-[(2-methylsulfonylphenyl)methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1,3-dihydroindol-2-one	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0150	uM
5-[[4-[(2-pyrrolidin-1-ylsulfonylphenyl)methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1,3-dihydroindol-2-one	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0170	uM
N-[3-[[[2-(3-bromo-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]-2-pyridinyl]-N-prop-2-enylmethanesulfonamide	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0195	uM
70692073	599633: Inhibition of PYK2 assessed as reduction in peptide substrate phosphorylation by fluorimetric method	ic50	0.0210	uM
4-N-[(1R,2R)-2-(dimethylamino)cyclopentyl]-2-N-[4-(S-methyl-N-propan-2-ylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine	599633: Inhibition of PYK2 assessed as reduction in peptide substrate phosphorylation by fluorimetric method	ic50	0.0220	uM
N-methyl-4-[[4-[[3-[methyl(methylsulfonyl)amino]pyrazin-2-yl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	2200416: Binding affinity to human recombinant PYK2 (amino acids 420-691) expressed in Escherichia coli, BL21 (DE3) assessed as equilibrium dissociation constant by SPR assay	kd	0.0240	uM
Brigatinib	2182808: Inhibition of human PTK2B using poly (Glu, Tyr)4:1 as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0240	uM
4-[[4-(2-methoxyanilino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzamide	1765254: Inhibition of Pyk2 (unknown origin) measured after 40 mins by HTRF	ic50	0.0245	uM
N-cyclopropyl-4-[[4-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	2200416: Binding affinity to human recombinant PYK2 (amino acids 420-691) expressed in Escherichia coli, BL21 (DE3) assessed as equilibrium dissociation constant by SPR assay	kd	0.0250	uM
4-N-[(1R,2R)-2-(dimethylamino)cyclopentyl]-2-N-(2-methyl-1,1-dioxo-3H-1,2-benzothiazol-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0250	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-(5-imidazo[1,2-a]pyridin-6-yl-1H-pyrazol-3-yl)urea	717755: Inhibition of PYK2 after 2hrs by fluorescence polarization assay	ic50	0.0250	uM
18-methylsulfonyl-28-(trifluoromethyl)-2,10,18,20,26,30,31-heptazahexacyclo[25.3.1.13,7.112,16.06,10.019,24]tritriaconta-1(30),3(33),4,6,12,14,16(32),19(24),20,22,27(31),28-dodecaen-11-one	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0260	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624732: Binding constant for PYK2 kinase domain	kd	0.0290	uM
4-N-[(1R,2R)-2-(dimethylamino)cyclopentyl]-2-N-[4-(N,S-dimethylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine	599634: Inhibition of PYK2 by PYK2-LI-COR cellular assay	ic50	0.0290	uM
15-methylsulfonyl-25-(trifluoromethyl)-2,10,15,17,23,27,28-heptazapentacyclo[22.3.1.13,7.06,10.016,21]nonacosa-1(27),3(29),4,6,16(21),17,19,24(28),25-nonaen-11-one	1333745: Inhibition of full length recombinant human N-terminal His6-tagged PYK2 expressed in baculovirus infected sf21 cells	ic50	0.0300	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425143: 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	0.0300	uM
N-methyl-N-[2-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]phenyl]methanesulfonamide;hydrochloride	319376: Inhibition of recombinant PYK2	ic50	0.0310	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[2-(pyrrolidine-1-carbonyl)-1H-indol-7-yl]urea	717755: Inhibition of PYK2 after 2hrs by fluorescence polarization assay	ic50	0.0310	uM
2-[[5-chloro-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]-N-methylbenzamide	1755630: Inhibition of pyk2 (unknown origin)	ic50	0.0330	uM
7-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0330	uM
N-[5-(6,7-dimethoxyquinolin-4-yl)oxy-2-pyridinyl]-2-oxo-1-phenyl-5-pyridin-3-ylpyridine-3-carboxamide	448365: Inhibition of human Pyk2 by HTRF assay	ic50	0.0330	uM
N-methyl-N-[2-[[[2-(4-methylsulfonylanilino)-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]phenyl]methanesulfonamide	410185: Inhibition of GST-tagged pyk2 assessed as inhibition of poly-Glu-Tyr phosphorylation	ic50	0.0350	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression, affects cotreatment	5
Air Pollutants	affects expression, increases abundance, decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Dexamethasone	increases expression, affects reaction, increases phosphorylation	3
sodium arsenite	increases phosphorylation, increases reaction, decreases expression	2
Doxorubicin	decreases expression, decreases reaction, increases phosphorylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
GSK-J4	increases expression	1
dicrotophos	increases expression	1
7-ketocholesterol	increases activity, increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
quercitrin	affects expression	1
beta-lapachone	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
tamibarotene	increases expression	1
1,2-bis(2-aminophenoxy)ethane N,N,N’,N’-tetraacetic acid acetoxymethyl ester	decreases reaction, increases phosphorylation	1
chromium hexavalent ion	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
manganese(III)-tetrakis(4-benzoic acid)porphyrin	decreases reaction, increases phosphorylation	1

ChEMBL screening assays

361 unique, capped per target: 360 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1024920	Binding	Binding affinity to human PYK2 at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem
CHEMBL1963760	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PTK2B	PubChem BioAssay data set

Cellosaurus cell lines

23 cell lines: 21 cancer cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A648	INT-MEL-12	Cancer cell line	Female
CVCL_B4KG	D18	Cancer cell line	Sex unspecified
CVCL_B7JF	EPN-PKM3	Spontaneously immortalized cell line	Male
CVCL_D1YM	Abcam A-549 PTK2B KO	Cancer cell line	Male
CVCL_D2CR	Abcam HCT 116 PTK2B KO	Cancer cell line	Male
CVCL_D2NZ	Abcam THP-1 PTK2B KO	Cancer cell line	Male
CVCL_D7YX	Ubigene A-549 PTK2B KO	Cancer cell line	Male
CVCL_D843	NZM007	Cancer cell line	Male
CVCL_D844	NZM007.2	Cancer cell line	Male
CVCL_D845	NZM007.4	Cancer cell line	Male

Clinical trials (associated diseases)

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