HCK

Summary

HCK (HCK proto-oncogene, Src family tyrosine kinase, HGNC:4840) is a protein-coding gene on chromosome 20q11.21, encoding Tyrosine-protein kinase HCK (P08631). Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell s….

The protein encoded by this gene is a member of the Src family of tyrosine kinases. This protein is primarily hemopoietic, particularly in cells of the myeloid and B-lymphoid lineages. It may help couple the Fc receptor to the activation of the respiratory burst. In addition, it may play a role in neutrophil migration and in the degranulation of neutrophils. Multiple isoforms with different subcellular distributions are produced due to both alternative splicing and the use of alternative translation initiation codons, including a non-AUG (CUG) codon.

Source: NCBI Gene 3055 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoinflammation with pulmonary and cutaneous vasculitis (Moderate, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 115 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes — 61 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002110

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4840
Approved symbol	HCK
Name	HCK proto-oncogene, Src family tyrosine kinase
Location	20q11.21
Locus type	gene with protein product
Status	Approved
Aliases	JTK9
Ensembl gene	ENSG00000101336
Ensembl biotype	protein_coding
OMIM	142370
Entrez	3055

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000262651, ENST00000375852, ENST00000375862, ENST00000470092, ENST00000486475, ENST00000518730, ENST00000520553, ENST00000629881

RefSeq mRNA: 6 — MANE Select: NM_002110 NM_001172129, NM_001172130, NM_001172131, NM_001172132, NM_001172133, NM_002110

CCDS: CCDS33460, CCDS54453, CCDS54455, CCDS54456

Canonical transcript exons

ENST00000375852 — 13 exons

Exon	Start	End
ENSE00001468583	32101317	32101856
ENSE00003486521	32079774	32079877
ENSE00003490553	32071662	32071782
ENSE00003517859	32052242	32052486
ENSE00003519607	32086628	32086807
ENSE00003544962	32099004	32099135
ENSE00003561437	32084391	32084543
ENSE00003579002	32074623	32074721
ENSE00003607915	32073716	32073818
ENSE00003635422	32073319	32073361
ENSE00003647034	32093863	32094016
ENSE00003662889	32088568	32088644
ENSE00003667821	32083894	32084043

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 99.08.

FANTOM5 (CAGE): breadth broad, TPM avg 42.4830 / max 2094.1838, expressed in 695 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184012	41.3885	690
184013	0.8633	198
184011	0.2312	148

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.08	gold quality
mononuclear cell	CL:0000842	99.00	gold quality
leukocyte	CL:0000738	98.99	gold quality
granulocyte	CL:0000094	98.94	gold quality
blood	UBERON:0000178	98.87	gold quality
spleen	UBERON:0002106	96.82	gold quality
bone marrow	UBERON:0002371	94.43	gold quality
vermiform appendix	UBERON:0001154	94.21	gold quality
trabecular bone tissue	UBERON:0002483	93.68	gold quality
middle frontal gyrus	UBERON:0002702	93.47	gold quality
bone marrow cell	CL:0002092	92.91	gold quality
periodontal ligament	UBERON:0008266	92.54	gold quality
frontal pole	UBERON:0002795	91.11	gold quality
upper lobe of left lung	UBERON:0008952	90.14	gold quality
upper lobe of lung	UBERON:0008948	89.68	gold quality
paraflocculus	UBERON:0005351	89.54	gold quality
right lung	UBERON:0002167	89.47	gold quality
lymph node	UBERON:0000029	89.30	gold quality
caecum	UBERON:0001153	89.19	gold quality
lung	UBERON:0002048	87.25	gold quality
palpebral conjunctiva	UBERON:0001812	87.21	gold quality
lower lobe of lung	UBERON:0008949	86.96	gold quality
layer of synovial tissue	UBERON:0007616	86.47	gold quality
decidua	UBERON:0002450	86.09	gold quality
epithelium of nasopharynx	UBERON:0001951	85.69	gold quality
right coronary artery	UBERON:0001625	85.40	gold quality
mucosa of transverse colon	UBERON:0004991	85.15	gold quality
amniotic fluid	UBERON:0000173	84.85	gold quality
gall bladder	UBERON:0002110	84.49	gold quality
Brodmann (1909) area 10	UBERON:0013541	84.33	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	495.23
E-CURD-122	yes	76.43
E-MTAB-6678	yes	27.41
E-MTAB-9221	yes	26.38
E-ANND-3	yes	25.98
E-HCAD-13	yes	24.30
E-MTAB-6701	yes	22.10
E-MTAB-9467	yes	18.73
E-MTAB-9067	yes	14.74
E-MTAB-8410	yes	14.21
E-CURD-88	yes	13.23
E-MTAB-9801	yes	6.24
E-MTAB-5061	no	498.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF6, PML, RARA, SP1, SPI1

miRNA regulators (miRDB)

18 targeting HCK, 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-4455	100.00	65.48	1587
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-4752	98.71	68.04	833
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-3654	96.43	66.55	646

Literature-anchored findings (GeneRIF, showing 40)

• Alternate use of a non-AUG (CUG), and an in-frame, downstream AUG translation initiation codon, results in the production of two isoforms with different subcellular localization. (PMID:10967098)
• A dominant negative form of Hck, in an interaction that is SH3 domain dependent, blocks HIV-1 Nef induced MHC class I downregulation. (PMID:11500821)
• SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo (PMID:11976726)
• The interaction of the Bcr-Abl tyrosine kinase with this protein is mediated by multiple binding domains. (PMID:12592324)
• These results suggest that CSF-induced and HIV-1-mediated regulation of Hck and C/EBPbeta represent the heterogeneous susceptibility of tissue macrophages to HIV-1 infection. (PMID:12900520)
• C3G and Hck interact physically and functionally in vivo to activate kinase-dependent and caspase-mediated apoptosis, which is independent of catalytic domain of C3G (PMID:14551197)
• SRC kinases LYN & HCK let engaged b2 integrins form focal-adhesion-like structures needed for stable shear-resistant PMN adhesion. SRC-dependent outside-in signalling is needed for integrin adhesiveness triggered by a classical chemoattractant like IL-8. (PMID:14969582)
• Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells. (PMID:15010462)
• In humans, the cytoplasmic domain of ADAM15v2 strongly interacts with Lck and Hck and regulates leukocyte function. (PMID:15263807)
• HIV-1 Nef interferes with M-CSF receptor signaling through Hck activation and thereby inhibits M-CSF functions in monocytes/macrophages. (PMID:15626739)
• data support the existence of multiple active conformations of Src family member Hck kinase that may generate unique downstream signals (PMID:16210316)
• The free energy surface shows that the N-terminal end of HCK acts as a reversible two-state conformational switch coupling the catalytic domain to the regulatory modules. (PMID:16271895)
• Data suggest that the insertion/deletion polymorphism could be a functional polymorphism of the Hck gene, may contribute to COPD pathogenesis and modify COPD-related phenotypes. (PMID:17024369)
• The structure of the HckSH3:PD1 complex reveals novel features of SH3 ligand binding and yields new insights into the structural basics of SH3-ligand interactions. (PMID:17141806)
• p73 is identified as a novel substrate and interacting partner of Hck and it regulates p73 through mechanisms that are dependent on either catalytic activity or protein interaction domains. (PMID:17535448)
• hematopoietic cell kinase (hct) phosphorylates fems-like tyrosine kinase 3(FLT3) in the JM region and inhibits its maturation (PMID:17668209)
• Nef perturbs the intracellular maturation and the trafficking of nascent Fms, through a unique mechanism that required both the activation of Hck and the aberrant spatial regulation of the active Hck (PMID:17893228)
• Alternate use of a non-AUG (CUG), and an in-frame, downstream AUG translation initiation codon, results in the production of 2 isoforms in mouse and human. (PMID:1875927)
• Hck has a nonredundant function as a key downstream signaling partner for Bcr-Abl and may represent a potential drug target in CML (PMID:18794796)
• HCK and BIN1 plays critical roles in AHI-1-mediated leukemic transformation of cutaneous T-Cell Lymphoma. (PMID:19211505)
• This finding establishes an intriguing link between the pathogenesis of Nef and a newly emerging concept that the Golgi-localized Src kinases regulate the Golgi function. (PMID:19585521)
• Taken together, PKR and Hck were critical for DON-induced ribosomal recruitment of p38, its subsequent phosphorylation, and, ultimately, p38-driven proinflammatory cytokine expression. (PMID:20181660)
• Nef participates in HIV-1-induced multinucleated giant cells formation via a p61Hck- and lysosomal enzyme-dependent pathway (PMID:20488787)
• Identification and biophysical assessment of the molecular recognition mechanisms between the human haemopoietic cell kinase Src homology domain 3 and ALG-2-interacting protein X. (PMID:20670214)
• BSS-SAXS reconstruction is used to reveal the structural organization of Hck in solution and the different shifts in the equilibrium population of assembly states upon the binding of different signaling peptides (PMID:20798061)
• Data show that the structures and relative orientations of the SH2 and SH3 domains down-regulated Hck. (PMID:20810664)
• Hck activation at the Golgi apparatus causes the HIV-1 Nef-induced c-Fms proto-oncogene N-glycosylation defect. (PMID:21567396)
• Hck acts as a key regulator controlling gene expression in alternatively activated monocytes/macrophages. (PMID:21878628)
• Loss of HCK is associated with acute promyelocytic leukemia. (PMID:21993313)
• we show that Hck, has a pre-eminent role in LPS/TLR4-induced TNF and IL-6 production. (PMID:22021612)
• There were significant differences in the genotype and allele distribution of -627 G/T polymorphism in Hck gene between cases and controls. (PMID:22185326)
• the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV-1 (PMID:22393415)
• This particular binding mode enables Hck SH3 to sense a specific non-canonical residue situated in the SH3 RT-loop of the kinase. (PMID:22641034)
• The SRC family tyrosine kinase HCK and the ETS family transcription factors SPIB and EHF regulate transcytosis across a human follicle-associated epithelium model. (PMID:23439650)
• Data indicate that combined treatment using SFK (LYN, HCK, or FGR) and c-KIT inhibitor dasatinib dasatinib and chemotherapy provides a novel approach to increasing p53 activity and enhancing targeting of acute myeloid leukemia (AML) stem cells. (PMID:23896410)
• Interaction between Nef and Hck is important for Nef-dependent modulation of viral infectivity. (PMID:24051604)
• Interaction with the Src homology (SH3-SH2) region of the Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment. (PMID:25122770)
• we provide evidence for involvement of HCK and FGR in FCRL4-mediated immunoregulation and for the functional importance of posttranslational modifications of the FCRL4 molecule. (PMID:25972488)
• HCK represents a novel target for therapeutic development in MYD88-mutated Waldenstrom macroglobulinemia and activated-B cell diffuse large B-cell lymphoma, and possibly other diseases driven by mutated MYD88. (PMID:27143257)
• three-dimensional (3D) QSAR pharmacophore models were generated for Hck based on experimentally known inhibitors. A best pharmacophore model, Hypo1, was developed with high correlation coefficient (0.975), Low RMS deviation (0.60) and large cost difference (49.31), containing three ring aromatic and one hydrophobic aliphatic feature (PMID:27485399)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hck	ENSDARG00000058647
mus_musculus	Hck	ENSMUSG00000003283
rattus_norvegicus	Hck	ENSRNOG00000009331

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), 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

Tyrosine-protein kinase HCK — P08631 (reviewed: P08631)

Alternative names: Hematopoietic cell kinase, Hemopoietic cell kinase, p59-HCK/p60-HCK, p59Hck, p61Hck

All UniProt accessions (5): P08631, H0Y3C5, H7BXG4, H7C5P9, J3KPD6

UniProt curated annotations — full annotation on UniProt →

Function. Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.

Subunit / interactions. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with VAV1, WAS and RAPGEF1. This interaction stimulates its tyrosine-kinase activity. Interacts with ARRB1 and ARRB2. Interacts with ADAM15. Interacts with FASLG. Interacts with CBL. Interacts with FCGR1A; the interaction may be indirect. Interacts with IL6ST. Interacts (via SH3 domain) with ELMO1. Interacts (via SH3 domain) with TP73. Interacts with YAP1. Interacts with ABL1 and ITGB1, and thereby recruits ABL1 to activated ITGB1. Interacts (via SH3 domain) with WDCP. (Microbial infection) Interacts (via SH3 domain) with HEV ORF3 protein. (Microbial infection) Interacts (via SH3 domain) with HIV-1 Nef and Vif.

Subcellular location. Lysosome. Membrane. Cell projection. Podosome membrane. Cytoplasm. Cytosol Cell membrane. Caveola. Cell junction. Focal adhesion. Cytoskeleton. Golgi apparatus. Cytoplasmic vesicle. Nucleus Cytoplasmic vesicle. Secretory vesicle. Cytosol.

Tissue specificity. Detected in monocytes and neutrophils (at protein level). Expressed predominantly in cells of the myeloid and B-lymphoid lineages. Highly expressed in granulocytes. Detected in tonsil.

Post-translational modifications. Phosphorylated on several tyrosine residues. Autophosphorylated. Becomes rapidly phosphorylated upon activation of the immunoglobulin receptors FCGR1A and FCGR2A. Phosphorylation by the BCR-ABL fusion protein mediates activation of HCK. Phosphorylation at Tyr-411 increases kinase activity. Phosphorylation at Tyr-522 inhibits kinase activity. Kinase activity is not required for phosphorylation at Tyr-522, suggesting that this site is a target of other kinases. Ubiquitinated by CBL, leading to its degradation via the proteasome. Isoform 2 palmitoylation at position 2 requires prior myristoylation. Palmitoylation at position 3 is required for caveolar localization of isoform 2.

Disease relevance. Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity. Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation. Autoinflammation with pulmonary and cutaneous vasculitis (AIPCV) [MIM:620296] An autosomal dominant disorder characterized by cutaneous vasculitis and chronic pulmonary inflammation that evolves to fibrosis. AIPCV manifests soon after birth with petechial skin lesions, followed by progressive pulmonary involvement causing restrictive lung disease and respiratory insufficiency. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Subject to autoinhibition, mediated by intramolecular interactions involving the SH2 and SH3 domains. Kinase activity is also regulated by phosphorylation at regulatory tyrosine residues. Phosphorylation at Tyr-411 is required for optimal activity. Phosphorylation at Tyr-522 inhibits kinase activity. Inhibited by PP1 and A-770041.

Domain organisation. The SH3 domain mediates binding to HIV-1 Nef.

Induction. Up-regulated during myeloid cell differentiation. The highest levels are detected in fully differentiated phagocytes. Up-regulated by IL2.

Miscellaneous. Initiates from a CTG codon. Initiates from a CTG codon.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P08631-1	1, p60-HCK, p61Hck	yes
P08631-2	2, p59-HCK, p59Hck
P08631-3	3
P08631-4	4

RefSeq proteins (6): NP_001165600, NP_001165601, NP_001165602, NP_001165603, NP_001165604, NP_002101* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000980	SH2	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
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR035851	HCK_SH2	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR050198	Non-receptor_tyrosine_kinases	Family

Pfam: PF00017, PF00018, PF07714

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 (97 total): strand 29, helix 20, mutagenesis site 9, modified residue 7, sequence conflict 6, sequence variant 5, turn 5, lipid moiety-binding region 3, domain 3, initiator methionine 2, splice variant 2, binding site 2, chain 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

40 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5H0B	X-RAY DIFFRACTION	1.65
5ZJ6	X-RAY DIFFRACTION	1.7
5H0H	X-RAY DIFFRACTION	1.72
5H0G	X-RAY DIFFRACTION	1.8
9BYJ	X-RAY DIFFRACTION	1.8
4U5W	X-RAY DIFFRACTION	1.86
5H09	X-RAY DIFFRACTION	1.95
1QCF	X-RAY DIFFRACTION	2
2HK5	X-RAY DIFFRACTION	2
3REA	X-RAY DIFFRACTION	2
4ORZ	X-RAY DIFFRACTION	2
5H0E	X-RAY DIFFRACTION	2.1
2C0T	X-RAY DIFFRACTION	2.15
3VS3	X-RAY DIFFRACTION	2.17
3VRZ	X-RAY DIFFRACTION	2.22
2C0I	X-RAY DIFFRACTION	2.3
3RBB	X-RAY DIFFRACTION	2.35
3VS6	X-RAY DIFFRACTION	2.37
3VS1	X-RAY DIFFRACTION	2.46
3VRY	X-RAY DIFFRACTION	2.48
1AD5	X-RAY DIFFRACTION	2.6
1BU1	X-RAY DIFFRACTION	2.6
3VS2	X-RAY DIFFRACTION	2.61
3NHN	X-RAY DIFFRACTION	2.61
8F2P	X-RAY DIFFRACTION	2.63
3VS4	X-RAY DIFFRACTION	2.75
5NUH	X-RAY DIFFRACTION	2.78
2C0O	X-RAY DIFFRACTION	2.85
4LUD	X-RAY DIFFRACTION	2.85
3VS5	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08631-F1	83.93	0.68

Antibody-complex structures (SAbDab): 1 — 4ORZ

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): 381 (proton acceptor)

Ligand- & substrate-binding residues (2): 268–276; 290

Post-translational modifications (10): 36, 51, 202, 209, 411, 462, 522, 2, 2, 3

Mutagenesis-validated functional residues (9):

Position	Phenotype
3	slight palmitoylation, cytoplasmic and caveolar localization; in isoform 1;.
3	abolishes palmitoylation and localization at the cell membrane.
23	myristoylation and palmitoylation are abolished, leading to entirely cytoplasmic localization; in isoform 2.
24	palmitoylation is abolished, some cytoplasmic and no calveolar localization; in isoform 2.
290	loss of kinase activity.
305	loss of kinase activity.
381	loss of kinase activity.
411	reduced catalytic activity and higher affinity for target peptides.
522	constitutively activated kinase, leading to cellular transformation.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-164944	Nef and signal transduction
R-HSA-2029481	FCGR activation
R-HSA-912631	Regulation of signaling by CBL
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-9674555	Signaling by CSF3 (G-CSF)
R-HSA-9680350	Signaling by CSF1 (M-CSF) in myeloid cells
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling
R-HSA-9706374	FLT3 signaling through SRC family kinases

MSigDB gene sets: 546 (showing top): GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, MCLACHLAN_DENTAL_CARIES_UP, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, MODULE_169, GOBP_REGULATION_OF_PODOSOME_ASSEMBLY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, MODULE_45, BIOCARTA_BARRESTIN_SRC_PATHWAY

GO Biological Process (36): leukocyte migration involved in immune response (GO:0002522), innate immune response-activating signaling pathway (GO:0002758), negative regulation of inflammatory response to antigenic stimulus (GO:0002862), protein phosphorylation (GO:0006468), inflammatory response (GO:0006954), cell adhesion (GO:0007155), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), integrin-mediated signaling pathway (GO:0007229), mesoderm development (GO:0007498), positive regulation of cell population proliferation (GO:0008284), regulation of cell shape (GO:0008360), peptidyl-tyrosine phosphorylation (GO:0018108), cytokine-mediated signaling pathway (GO:0019221), cell differentiation (GO:0030154), positive regulation of actin filament polymerization (GO:0030838), lipopolysaccharide-mediated signaling pathway (GO:0031663), regulation of actin cytoskeleton organization (GO:0032956), intracellular signal transduction (GO:0035556), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), negative regulation of apoptotic process (GO:0043066), leukocyte degranulation (GO:0043299), respiratory burst after phagocytosis (GO:0045728), protein autophosphorylation (GO:0046777), regulation of inflammatory response (GO:0050727), regulation of phagocytosis (GO:0050764), defense response to Gram-positive bacterium (GO:0050830), obsolete regulation of DNA-binding transcription factor activity (GO:0051090), type II interferon-mediated signaling pathway (GO:0060333), regulation of podosome assembly (GO:0071801), immune system process (GO:0002376), exocytosis (GO:0006887), phagocytosis (GO:0006909), response to stress (GO:0006950), innate immune response (GO:0045087), leukocyte migration (GO:0050900), cellular response to lipid (GO:0071396)

GO Molecular Function (11): phosphotyrosine residue binding (GO:0001784), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), lipid binding (GO:0008289), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (17): nucleus (GO:0005634), lysosome (GO:0005764), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), caveola (GO:0005901), focal adhesion (GO:0005925), cytoplasmic side of plasma membrane (GO:0009898), transport vesicle (GO:0030133), cell projection (GO:0042995), cytoplasm (GO:0005737), actin filament (GO:0005884), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), membrane raft (GO:0045121), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Cytokine Signaling in Immune system	2
The role of Nef in HIV-1 replication and disease pathogenesis	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Leishmania phagocytosis	1
Signaling by CSF3 (G-CSF)	1
FLT3 Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell surface receptor signaling pathway	3
cytoplasm	3
intracellular anatomical structure	2
binding	2
intracellular membrane-bounded organelle	2
endomembrane system	2
immune effector process	1
immune response	1
leukocyte migration	1
activation of innate immune response	1
immune response-activating signaling pathway	1
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
phosphorylation	1
protein modification process	1
defense response	1
cellular process	1
enzyme-linked receptor protein signaling pathway	1
tissue development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
protein phosphorylation	1
peptidyl-tyrosine modification	1
cellular response to cytokine stimulus	1
cellular developmental process	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
cellular response to lipopolysaccharide	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1

Protein interactions and networks

STRING

3331 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCK	LCK	P06239	775
HCK	STAT3	P40763	746
HCK	WAS	P42768	742
HCK	CDC37L1	Q7L3B6	678
HCK	TNK2	Q07912	664
HCK	FCER1G	P30273	658
HCK	RAPGEF1	Q13905	650
HCK	PTPN1	P18031	642
HCK	WIPF1	O43516	636
HCK	CBL	P22681	616
HCK	VAV1	P15498	613
HCK	LCP2	Q13094	606
HCK	CRK	P46108	598
HCK	FYN	P06241	597
HCK	ARL2	P36404	591

IntAct

177 interactions, top by confidence:

A	B	Type	Score
KHDRBS1	HCK	psi-mi:“MI:0915”(physical association)	0.780
HCK	KHDRBS1	psi-mi:“MI:0407”(direct interaction)	0.780
HCK	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.780
HCK		psi-mi:“MI:0915”(physical association)	0.730
	HCK	psi-mi:“MI:0915”(physical association)	0.730
	HCK	psi-mi:“MI:0217”(phosphorylation reaction)	0.730
WAS	HCK	psi-mi:“MI:0915”(physical association)	0.720
HCK	WAS	psi-mi:“MI:0915”(physical association)	0.720
ADAM15	HCK	psi-mi:“MI:0407”(direct interaction)	0.710
PDCD6IP	HCK	psi-mi:“MI:0915”(physical association)	0.710
PDCD6IP	HCK	psi-mi:“MI:0407”(direct interaction)	0.710
ADAM15	HCK	psi-mi:“MI:0915”(physical association)	0.710
SOS1	HCK	psi-mi:“MI:0915”(physical association)	0.690
HCK	SOS1	psi-mi:“MI:2364”(proximity)	0.690
SOS1	HCK	psi-mi:“MI:2364”(proximity)	0.690
SOS1	HCK	psi-mi:“MI:0407”(direct interaction)	0.690
HCK	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (216): SPRR2A (Reconstituted Complex), MTUS2 (Two-hybrid), GOPC (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-9 (Two-hybrid), NOTCH2NL (Two-hybrid), HCK (Two-hybrid), MDM2 (Protein-peptide), HCK (Synthetic Lethality), NGEF (Two-hybrid), PIK3R3 (Two-hybrid), FRS3 (Two-hybrid), LETMD1 (Two-hybrid), OLIG1 (Two-hybrid), PTK2 (Two-hybrid)

ESM2 similar proteins: A0JNB0, A1A5H8, A1Y2K1, F1LM93, F1RDG9, P00523, P00524, P00525, P00526, P00527, P05480, P06239, P06240, P06241, P07947, P07948, P08103, P08631, P09324, P09769, P10936, P12931, P13115, P13116, P13406, P14084, P14085, P14234, P17713, P25020, P27446, P27447, P31693, P39688, P42683, P50545, P63185, Q01621, Q02977, Q04736

Diamond homologs: A0JNB0, A1A5H8, A1Y2K1, F1LM93, F1RDG9, G5EE56, O45539, P00519, P00520, P00521, P00522, P00523, P00524, P00525, P00526, P00527, P00528, P00544, P03949, P05480, P06239, P06240, P06241, P07947, P07948, P08103, P08630, P08631, P09324, P09769, P10447, P10936, P12931, P13115, P13116, P13406, P14084, P14085, P14234, P15054

SIGNOR signaling

37 interactions.

A	Effect	B	Mechanism
HCK	up-regulates	ADAM15	phosphorylation
HCK	unknown	ADAM15	phosphorylation
HCK	up-regulates	ELMO1	phosphorylation
HCK	up-regulates	RAPGEF1	phosphorylation
HCK	“up-regulates activity”	HCK	phosphorylation
HCK	“up-regulates activity”	BCR-ABL	phosphorylation
HCK	“down-regulates activity”	TBK1	phosphorylation
HCK	“up-regulates activity”	GLI1	phosphorylation
HCK	up-regulates	BCR-ABL	phosphorylation
HCK	down-regulates	HCK	phosphorylation
HCK	up-regulates	HCK	phosphorylation
HCK	unknown	CBL	phosphorylation
HCK	“up-regulates activity”	PLCG1	phosphorylation
HCK	“up-regulates activity”	PLCG2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
Constitutive Signaling by EGFRvIII	5	50.3×	2e-06
Signaling by ERBB2 ECD mutants	5	47.3×	2e-06
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	6	43.9×	4e-07
Role of LAT2/NTAL/LAB on calcium mobilization	5	42.3×	3e-06
DAP12 signaling	8	41.5×	7e-09
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	40.2×	4e-06
Signaling by ALK	5	40.2×	4e-06
Signaling by ERBB2 KD Mutants	6	35.7×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	9	27.9×	3e-08
B cell receptor signaling pathway	5	25.1×	2e-04
cell surface receptor protein tyrosine kinase signaling pathway	9	19.5×	4e-07
T cell receptor signaling pathway	9	17.1×	9e-07
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	15.8×	2e-04
protein autophosphorylation	7	12.7×	2e-04
male gonad development	5	9.8×	6e-03
actin filament organization	6	8.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	69
Likely benign	18
Benign	7

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2446380	NM_002110.5(HCK):c.1545C>A (p.Tyr515Ter)	Pathogenic
809243	NM_002110.5(HCK):c.1555G>T (p.Glu519Ter)	Likely pathogenic

SpliceAI

2287 predictions. Top by Δscore:

Variant	Effect	Δscore
20:32071660:A:AG	acceptor_gain	1.0000
20:32071660:AG:A	acceptor_gain	1.0000
20:32071660:AGGAT:A	acceptor_gain	1.0000
20:32071661:G:GG	acceptor_gain	1.0000
20:32071661:GG:G	acceptor_gain	1.0000
20:32071661:GGAT:G	acceptor_gain	1.0000
20:32071661:GGATG:G	acceptor_gain	1.0000
20:32071779:GCCG:G	donor_gain	1.0000
20:32071780:CCGGT:C	donor_loss	1.0000
20:32071781:CGG:C	donor_loss	1.0000
20:32071782:GGT:G	donor_loss	1.0000
20:32071783:G:GG	donor_gain	1.0000
20:32071783:GT:G	donor_loss	1.0000
20:32071784:T:A	donor_loss	1.0000
20:32071785:GAG:G	donor_loss	1.0000
20:32073313:CCACA:C	acceptor_loss	1.0000
20:32073357:GGAGG:G	donor_gain	1.0000
20:32073358:GAGGG:G	donor_gain	1.0000
20:32073360:GG:G	donor_gain	1.0000
20:32073361:GG:G	donor_gain	1.0000
20:32073714:A:AG	acceptor_gain	1.0000
20:32073714:AGCAG:A	acceptor_gain	1.0000
20:32073715:G:GC	acceptor_gain	1.0000
20:32073715:GC:G	acceptor_gain	1.0000
20:32073715:GCA:G	acceptor_gain	1.0000
20:32073715:GCAGG:G	acceptor_gain	1.0000
20:32073806:T:TA	donor_gain	1.0000
20:32073807:G:GA	donor_gain	1.0000
20:32073814:GAGGA:G	donor_gain	1.0000
20:32073815:AGGA:A	donor_gain	1.0000

AlphaMissense

3472 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:32079857:G:C	R171P	1.000
20:32084525:T:C	F273L	1.000
20:32084527:T:A	F273L	1.000
20:32084527:T:G	F273L	1.000
20:32086660:A:G	K290E	1.000
20:32086662:G:C	K290N	1.000
20:32086662:G:T	K290N	1.000
20:32093905:C:G	H379D	1.000
20:32093909:G:C	R380P	1.000
20:32093912:A:C	D381A	1.000
20:32093912:A:G	D381G	1.000
20:32093912:A:T	D381V	1.000
20:32093913:C:A	D381E	1.000
20:32093913:C:G	D381E	1.000
20:32093915:T:A	L382H	1.000
20:32093915:T:C	L382P	1.000
20:32093928:C:A	N386K	1.000
20:32093928:C:G	N386K	1.000
20:32093965:G:C	D399H	1.000
20:32093966:A:C	D399A	1.000
20:32093966:A:G	D399G	1.000
20:32093966:A:T	D399V	1.000
20:32093967:C:A	D399E	1.000
20:32093967:C:G	D399E	1.000
20:32093975:T:C	L402P	1.000
20:32099024:T:A	W423R	1.000
20:32099024:T:C	W423R	1.000
20:32099026:G:C	W423C	1.000
20:32099026:G:T	W423C	1.000
20:32099057:T:C	F434L	1.000

dbSNP variants (sampled 300 via entrez): RS1000050631 (20:32077049 A>C,G), RS1000061017 (20:32073612 A>G), RS1000129920 (20:32095852 G>T), RS1000216350 (20:32083149 A>G), RS1000285574 (20:32079270 G>A), RS1000393232 (20:32085968 T>A), RS1000416073 (20:32085474 A>G), RS1000468535 (20:32085761 G>A), RS1000481849 (20:32076114 G>A), RS1000545780 (20:32084320 C>A,T), RS1000603433 (20:32075748 A>G,T), RS1000652888 (20:32078159 C>T), RS1000671415 (20:32084672 C>T), RS1000696638 (20:32079626 A>T), RS1000970603 (20:32096633 C>G)

Disease associations

OMIM: gene MIM:142370 | disease phenotypes: MIM:620296

GenCC curated gene-disease

Disease	Classification	Inheritance
autoinflammation with pulmonary and cutaneous vasculitis	Moderate	Autosomal dominant

Mondo (1): autoinflammation with pulmonary and cutaneous vasculitis (MONDO:0957204)

Orphanet (0):

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000967	Petechiae
HP:0000979	Purpura
HP:0001744	Splenomegaly
HP:0001903	Anemia
HP:0002091	Restrictive ventilatory defect
HP:0002240	Hepatomegaly
HP:0002788	Recurrent upper respiratory tract infections
HP:0002878	Respiratory failure
HP:0003623	Neonatal onset
HP:0006515	Interstitial pneumonitis
HP:0200029	Vasculitis in the skin

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001725_63	Inflammatory bowel disease	6.000000e-10
GCST003720_4	Migraine	1.000000e-08
GCST007611_4	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	4.000000e-08
GCST010796_2354	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_2355	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010988_322	Adult body size	1.000000e-08
GCST90013406_103	Liver enzyme levels (alkaline phosphatase)	4.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363074 (PROTEIN FAMILY), CHEMBL3234 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

61 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 530,181 (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
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL939	GEFITINIB	4
CHEMBL1908391	MASITINIB	3
CHEMBL217092	SARACATINIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL3544983	TESEVATINIB	3
CHEMBL377300	BRIVANIB	3
CHEMBL415049	BARASERTIB	3
CHEMBL483158	ALISERTIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL522892	DOVITINIB	3

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Src family

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
compound 2 [PMID: 15546730]	Inhibition	8.7	pIC50
eCF506	Inhibition	8.55	pIC50
PP121	Inhibition	8.1	pIC50
pexmetinib	Inhibition	7.59	pIC50
ibrutinib	Inhibition	7.54	pIC50

Binding affinities (BindingDB)

61 measured of 92 human assays (105 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
IBRUTINIB	IC50	0.8 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]prop-2-enamide	IC50	1.1 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
Staurosporine	KD	1.7 nM
3-[[2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridin-7-yl]amino]phenol	IC50	5.1 nM	US-9062066: Anti-inflammatory compound having inhibitory activity against multiple tyrosine kinases and pharmaceutical composition containing same
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	IC50	10 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
N-[4-[4-[[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]carbamoylamino]naphthalen-1-yl]oxy-2-pyridinyl]-2-methoxyacetamide	IC50	12 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-[3-(1-methylcyclopropyl)-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	19 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[2,3-dichloro-4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]phenyl]urea	IC50	23 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	24 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-[4-(hydroxymethyl)-3-methoxyphenyl]pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	24 nM	US-8933228: Respiratory formulations and compounds for use therein
BMS-354825	KD	27 nM
1-[3-tert-butyl-1-[4-(methylsulfamoylmethyl)phenyl]pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	29 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-[4-(hydroxymethyl)phenyl]pyrazol-5-yl]-3-[2,3-dichloro-4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]phenyl]urea	IC50	35 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[1-(4-methylphenyl)-3-propan-2-ylpyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	39 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(5-methylthiophen-2-yl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	41 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	43 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-[6-(hydroxymethyl)-3-pyridinyl]pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	44 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	45 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-hydroxyphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	45 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylsulfonylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	47 nM	US-8933228: Respiratory formulations and compounds for use therein
1-cyclobutyl-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, PP494	IC50	47 nM
1-cyclopentyl-3-(H-imidazo[1,2-a]pyridin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, PP162	IC50	53 nM
1-[4-(2-anilinopyrimidin-4-yl)oxynaphthalen-1-yl]-3-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]urea	IC50	60 nM	US-9724347: 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl) ureas as P38 MAP knase inhibitors
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-[(2-oxo-1,7a-dihydroimidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	67 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	72 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(2-oxo-1,7a-dihydroimidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	74 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylsulfanylphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	74 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(3,4-dichlorophenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	89 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-methylidene-3-oxopyrido[2,3-b]pyrazin-8-yl)oxynaphthalen-1-yl]urea	IC50	99 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[4-(2-methylidene-3-oxopyrido[2,3-b]pyrazin-8-yl)oxynaphthalen-1-yl]urea	IC50	100 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[4-[(2-oxo-1,3,3a,4,5,6,7,7a-octahydroimidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	119 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(6-methoxy-3-pyridinyl)pyrazol-5-yl]-3-[4-[(1-methyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	126 nM	US-8933228: Respiratory formulations and compounds for use therein
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[8-[(2-oxo-1,3,3a,4,5,6,7,7a-octahydroimidazo[4,5-b]pyridin-7-yl)oxy]quinolin-5-yl]urea	IC50	180 nM	US-8933228: Respiratory formulations and compounds for use therein
PKC-412	KD	190 nM
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)methoxy]naphthalen-1-yl]urea	IC50	193 nM	US-8933228: Respiratory formulations and compounds for use therein
1-(3-tert-butyl-1-phenylpyrazol-5-yl)-3-[8-[(2-oxo-1,7a-dihydroimidazo[4,5-b]pyridin-7-yl)oxy]quinolin-5-yl]urea	IC50	214 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-chlorophenyl)pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	237 nM	US-8933228: Respiratory formulations and compounds for use therein
4-[[7-[2,6-bis(fluoranyl)phenyl]-9-chloranyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	KD	300 nM
1-[3-tert-butyl-1-[4-(hydroxymethyl)phenyl]pyrazol-5-yl]-3-[4-[(3-oxo-8aH-pyrido[2,3-b]pyrazin-8-yl)oxy]naphthalen-1-yl]urea	IC50	318 nM	US-8933228: Respiratory formulations and compounds for use therein
6-(2-((2,6-Dimethylphenyl)amino)-1H-imidazol-1-yl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)pyrimidin-4-amine	IC50	338 nM	US-10287268: Imidazolyl kinase inhibitors and uses thereof
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[4-[(1-ethyl-2-oxo-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	348 nM	US-8933228: Respiratory formulations and compounds for use therein
N-[4-[[4-[[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]-2-pyridinyl]-2-methoxyacetamide	IC50	402 nM	US-8933228: Respiratory formulations and compounds for use therein
1-[3-tert-butyl-1-(4-methoxyphenyl)pyrazol-5-yl]-3-[4-[(2-oxo-1-propan-2-yl-3H-imidazo[4,5-b]pyridin-7-yl)oxy]naphthalen-1-yl]urea	IC50	495 nM	US-8933228: Respiratory formulations and compounds for use therein
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-[(8-oxo-1,2,3,4,5,6,7,9-octahydropurin-6-yl)oxy]naphthalen-1-yl]urea	IC50	539 nM	US-8933228: Respiratory formulations and compounds for use therein
3-[4-(benzylamino)-3-methoxyphenyl]-1-[2-[4-(dimethylamino)piperidin-1-yl]ethyl]pyrazolo[3,4-d]pyrimidin-4-amine	IC50	550 nM	US-10294227: Compounds
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM

ChEMBL bioactivities

624 potent at pChembl≥5 of 653 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.96	IC50	0.11	nM	PONATINIB
9.74	IC50	0.18	nM	CHEMBL1241676
9.59	IC50	0.257	nM	CHEMBL4075002
9.59	IC50	0.26	nM	CHEMBL4075002
9.50	Ki	0.3162	nM	DASATINIB
9.46	Kd	0.35	nM	DASATINIB
9.40	IC50	0.4	nM	CHEMBL45177
9.37	IC50	0.4266	nM	CHEMBL45177
9.37	IC50	0.43	nM	CHEMBL45177
9.23	IC50	0.59	nM	CHEMBL6030654
9.23	IC50	0.59	nM	CHEMBL5941829
9.14	IC50	0.73	nM	CHEMBL5760397
9.00	IC50	1	nM	CHEMBL3647967
8.79	IC50	1.64	nM	CHEMBL5846343
8.74	IC50	1.8	nM	CHEMBL4208645
8.72	IC50	1.9	nM	STAUROSPORINE
8.71	IC50	1.94	nM	CHEMBL5829834
8.70	IC50	2	nM	CHEMBL364623
8.70	IC50	2	nM	CHEMBL1090979
8.70	IC50	2	nM	CHEMBL1241484
8.70	IC50	2	nM	CHEMBL1241581
8.65	IC50	2.23	nM	STAUROSPORINE
8.62	IC50	2.42	nM	CHEMBL5854945
8.61	IC50	2.43	nM	CHEMBL6027766
8.55	IC50	2.8	nM	CHEMBL4568087
8.52	IC50	3	nM	CHEMBL3695574
8.52	IC50	3	nM	CHEMBL3695593
8.52	IC50	3	nM	CHEMBL1214131
8.52	IC50	3	nM	CHEMBL3695569
8.52	IC50	3	nM	CHEMBL3695579
8.52	IC50	3	nM	CHEMBL3695583
8.52	IC50	3	nM	CHEMBL1214132
8.52	IC50	3	nM	CHEMBL3695592
8.52	IC50	3	nM	CHEMBL1214134
8.52	IC50	3	nM	CHEMBL4515441
8.52	IC50	3.03	nM	STAUROSPORINE
8.52	IC50	3	nM	CHEMBL4798527
8.49	IC50	3.2	nM	BOSUTINIB
8.48	Kd	3.3	nM	CHEMBL386051
8.47	Kd	3.4	nM	BOSUTINIB
8.46	IC50	3.467	nM	CHEMBL4095434
8.46	IC50	3.5	nM	CHEMBL4095434
8.43	IC50	3.7	nM	IBRUTINIB
8.43	IC50	3.7	nM	CHEMBL4066401
8.40	IC50	4	nM	CHEMBL3695578
8.40	IC50	4	nM	CHEMBL3695591
8.40	IC50	4	nM	CHEMBL3695586
8.40	IC50	4	nM	CHEMBL3695580
8.40	IC50	4	nM	CHEMBL3695581
8.40	IC50	4	nM	CHEMBL3695577

PubChem BioAssay actives

494 with measured affinity, of 1930 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
Ponatinib	1716394: Binding affinity to human HCK using KVEKIGEGTYGVVYK as substrate by radiometric hotspot kinase assay	ic50	0.0001	uM
5-(4-amino-1-cyclopentylpyrazolo[3,4-d]pyrimidin-3-yl)-2-chlorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0002	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	435311: Binding constant for HCK kinase domain	kd	0.0003	uM
5-(4-phenoxyphenyl)-7-[4-(4-propan-2-ylpiperazin-1-yl)cyclohexyl]pyrrolo[2,3-d]pyrimidin-4-amine	1487300: Inhibition of HCK (unknown origin)	ic50	0.0003	uM
7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0004	uM
1-[4-(4-methylpiperazin-1-yl)cyclohexyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine	1872714: Inhibition of HCK (unknown origin)	ic50	0.0005	uM
N-[3-[2-[4-(2-aminoethoxy)anilino]quinazolin-6-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1799897: Fluorescence Assay from Article 10.1021/cb300623a: “A Hexylchloride-Based Catch-and-Release System for Chemical Proteomic Applications.”	ic50	0.0005	uM
tert-butyl N-[4-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]carbamate	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0010	uM
(2S)-2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]-3-hydroxypropanoic acid	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0018	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	1531717: Inhibition of human HCK using KVEKIGEGTYGVVYK as substrate by [gamma-33P]-ATP assay	ic50	0.0019	uM
N-(2-chloro-6-methylphenyl)-2-[(2,6-dimethylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide	240535: inhibitory activity against Hck kinase	ic50	0.0020	uM
3-(4-amino-3-methoxyphenyl)-1-cyclopentylpyrazolo[3,4-d]pyrimidin-4-amine	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0020	uM
5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-2-chlorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0020	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637083: Inhibition of full-length human N-terminal GST-tagged HCK expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.0028	uM
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	1734744: Inhibition of human HCK (230 to 497 residues) using GGMEDIYFEFMGGKKK as substrate incubated for 40 mins in presence of [gamma33P-ATP] by radiometric scintillation counting analysis	ic50	0.0030	uM
N-(2-chloro-6-methylphenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-4-[2-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamide	1560506: Inhibition of HCK (unknown origin)	ic50	0.0030	uM
Bosutinib	507439: Inhibition of HCK	ic50	0.0032	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624857: Binding constant for HCK kinase domain	kd	0.0033	uM
2-[4-[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]piperazin-1-yl]ethanol	1487300: Inhibition of HCK (unknown origin)	ic50	0.0035	uM
2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]acetic acid	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0037	uM
Ibrutinib	1714868: Inhibition of HCK (unknown origin)	ic50	0.0037	uM
5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-2-bromophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0040	uM
(2S)-2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]-4-methylpentanoic acid	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0044	uM
3-(4-amino-1-cyclopentylpyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0044	uM
5-(4-amino-1-cyclopentylpyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0045	uM
1-cyclopentyl-3-(1H-indol-6-yl)pyrazolo[3,4-d]pyrimidin-4-amine	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0050	uM
1-tert-butyl-3-(4-chlorophenyl)pyrazolo[3,4-d]pyrimidin-4-amine	325799: Inhibition of Hck	ic50	0.0050	uM
5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-2-methylphenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0051	uM
(3S)-3-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]oxolan-2-one	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0054	uM
1-cyclopentyl-3-(1H-indol-5-yl)pyrazolo[3,4-d]pyrimidin-4-amine	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0054	uM
5-[4-amino-1-(3-methylcyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0057	uM
5-(4-amino-1-cyclobutylpyrazolo[3,4-d]pyrimidin-3-yl)-2-chlorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0058	uM
6-amino-7-(4-phenoxyphenyl)-9-[(3S)-1-prop-2-enoylpiperidin-3-yl]purin-8-one	1425017: 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	0.0060	uM
(2R)-2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]-3-hydroxypropanoic acid	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0063	uM
N-[3-[[3-[6-[4-[2-[[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetyl]amino]ethoxy]anilino]pyrimidin-4-yl]-2-pyridinyl]amino]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1799543: In Vitro Activity Assay from Article 10.1016/j.chembiol.2010.01.008: “Affinity reagents that target a specific inactive form of protein kinases.”	ic50	0.0063	uM
(2S)-2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]propanoic acid	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0069	uM
(2S)-2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]-3-(4-hydroxyphenyl)propanoic acid	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0074	uM
(2S)-2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]-3-phenylpropanoic acid	1366202: Inhibition of recombinant human HCK SH3-SH2-KD (75 to 526 residues) after 20 mins by mobility shift assay	ic50	0.0075	uM
2-[[4-[4-amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]acetamide	1487300: Inhibition of HCK (unknown origin)	ic50	0.0076	uM
3-[7-amino-3-[4-(4-methylpiperazin-1-yl)phenyl]pyrazolo[1,5-a]pyrimidin-6-yl]phenol	484554: Inhibition of HCK	ic50	0.0080	uM
1-cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[3,4-d]pyrimidin-4-amine	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0080	uM
5-[4-amino-1-[(3R)-oxolan-3-yl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-chlorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0080	uM
N-[3-[[3-[4-[4-[2-[5-[3-(2-fluoro-10,12-dimethyl-1-aza-3-azonia-2-boratricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)propanoylamino]pentanoylamino]ethoxy]anilino]-1,3,5-triazin-2-yl]-2-pyridinyl]amino]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1799543: In Vitro Activity Assay from Article 10.1016/j.chembiol.2010.01.008: “Affinity reagents that target a specific inactive form of protein kinases.”	kd	0.0087	uM
5-[4-amino-1-[(3S)-oxolan-3-yl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-chlorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0088	uM
5-(4-phenoxyphenyl)-7-[4-(pyridin-4-ylmethylamino)cyclohexyl]pyrrolo[2,3-d]pyrimidin-4-amine	1487300: Inhibition of HCK (unknown origin)	ic50	0.0089	uM
5-(4-amino-1-cyclobutylpyrazolo[3,4-d]pyrimidin-3-yl)-2-bromophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0089	uM
N-[3-[[1-(6-aminopyrimidin-4-yl)benzimidazol-2-yl]amino]-4-methylphenyl]-3-chloro-4-[(4-ethylpiperazin-1-yl)methyl]benzamide	469071: Inhibition of HCK	ic50	0.0090	uM
3-[2-[2-amino-5-(1-methylpyrazol-4-yl)-3-pyridinyl]ethynyl]-N-[3,5-bis(trifluoromethyl)phenyl]-4-methylbenzamide	1779903: Inhibition of human recombinant HCK (230 to 497) by radiometric scintillation counting analysis	ic50	0.0090	uM
tert-butyl 5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)indole-1-carboxylate	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0090	uM
5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol	507080: Inhibition of recombinant HCK by radioactive phosphotransfer assay in presence of 10 uM ATP	ic50	0.0092	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Tretinoin	increases expression	3
sodium arsenite	increases reaction, affects cotreatment, decreases expression, affects binding	2
entinostat	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Nickel	decreases expression, increases expression	2
3,4,5-trimethoxybenzaldehyde	affects binding, decreases activity	1
Asian ginseng	decreases expression, decreases reaction, affects cotreatment	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases phosphorylation	1
deoxynivalenol	increases phosphorylation	1
lead acetate	decreases expression, affects cotreatment	1
4-bis(2-chloroethyl)aminobenzaldehyde	affects binding, decreases reaction, decreases activity, decreases phosphorylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
sulforaphane	increases expression	1
chromous chloride	affects cotreatment, decreases expression	1
cobaltous chloride	increases expression	1
pyrrolidine dithiocarbamic acid	increases expression, affects cotreatment, decreases reaction	1
chromic oxide	affects cotreatment, decreases expression	1
bathocuproine sulfonate	affects cotreatment, decreases reaction, increases expression	1
aflatoxin B2	increases methylation	1
triphenyltin	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
clothianidin	increases expression	1

ChEMBL screening assays

431 unique, capped per target: 429 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5719121	Binding	Inhibition of Src family in human RPMI-8226 cells assessed as reduction of cell growth incubated for 72 hrs by CellTiter 96 aqueous one solution cell proliferation assay	Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma. — Oncotarget
CHEMBL1963709	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: HCK	PubChem BioAssay data set
CHEMBL4414993	ADMET	Inhibition of human HCK at 1 uM using poly[Glu:Tyr] (4:1) as substrate preincubated for 15 to 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D9G2	Ubigene HEK293 HCK KO	Transformed cell line	Female
CVCL_SQ96	HAP1 HCK (-) 1	Cancer cell line	Male
CVCL_SQ97	HAP1 HCK (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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