ZAP70

Summary

ZAP70 (zeta chain of T cell receptor associated protein kinase 70, HGNC:12858) is a protein-coding gene on chromosome 2q11.2, encoding Tyrosine-protein kinase ZAP-70 (P43403). Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.

This gene encodes an enzyme belonging to the protein tyrosine kinase family, and it plays a role in T-cell development and lymphocyte activation. This enzyme, which is phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn. This enzyme is also essential for thymocyte development. Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells. Two transcript variants that encode different isoforms have been found for this gene.

Source: NCBI Gene 7535 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency due to ZAP70 deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 577 total — 24 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes — 14 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001079

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12858
Approved symbol	ZAP70
Name	zeta chain of T cell receptor associated protein kinase 70
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	ZAP-70, STD
Ensembl gene	ENSG00000115085
Ensembl biotype	protein_coding
OMIM	176947
Entrez	7535

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000264972, ENST00000451498, ENST00000463643, ENST00000483781, ENST00000487283, ENST00000489250, ENST00000495754, ENST00000498836, ENST00000698508, ENST00000698509, ENST00000718250, ENST00000885385, ENST00000885386, ENST00000885387

RefSeq mRNA: 3 — MANE Select: NM_001079 NM_001079, NM_001378594, NM_207519

CCDS: CCDS33254, CCDS33255

Canonical transcript exons

ENST00000264972 — 14 exons

Exon	Start	End
ENSE00001267184	97739375	97739860
ENSE00001346286	97713916	97713994
ENSE00001915964	97713576	97713674
ENSE00003467221	97735250	97735456
ENSE00003502647	97733297	97733343
ENSE00003503894	97733544	97733595
ENSE00003510686	97724016	97724438
ENSE00003540216	97725092	97725252
ENSE00003547939	97737995	97738107
ENSE00003599670	97737473	97737665
ENSE00003618162	97732883	97733021
ENSE00003637033	97733125	97733212
ENSE00003638273	97737757	97737897
ENSE00003646213	97734520	97734712

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 99.28.

FANTOM5 (CAGE): breadth broad, TPM avg 9.6180 / max 696.4163, expressed in 290 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21520	5.6167	226
21521	2.2848	140
21527	0.4039	56
21524	0.2428	76
21519	0.2245	77
21526	0.2123	49
21525	0.1943	60
21523	0.1877	66
21522	0.1532	65
21518	0.0525	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.28	gold quality
lymph node	UBERON:0000029	93.72	gold quality
blood	UBERON:0000178	93.26	gold quality
spleen	UBERON:0002106	92.98	gold quality
vermiform appendix	UBERON:0001154	90.38	gold quality
thymus	UBERON:0002370	88.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.77	gold quality
caecum	UBERON:0001153	83.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.57	gold quality
gall bladder	UBERON:0002110	82.61	gold quality
small intestine	UBERON:0002108	82.39	gold quality
upper lobe of left lung	UBERON:0008952	81.98	gold quality
mucosa of transverse colon	UBERON:0004991	81.53	gold quality
bone marrow cell	CL:0002092	80.01	gold quality
tonsil	UBERON:0002372	79.81	gold quality
upper lobe of lung	UBERON:0008948	79.24	gold quality
bone marrow	UBERON:0002371	79.04	gold quality
right lobe of liver	UBERON:0001114	78.23	gold quality
right lung	UBERON:0002167	78.13	gold quality
right uterine tube	UBERON:0001302	76.89	gold quality
omental fat pad	UBERON:0010414	76.41	gold quality
peritoneum	UBERON:0002358	76.31	gold quality
adipose tissue of abdominal region	UBERON:0007808	75.80	gold quality
superficial temporal artery	UBERON:0001614	75.37	silver quality
body of stomach	UBERON:0001161	74.90	gold quality
right coronary artery	UBERON:0001625	74.66	gold quality
transverse colon	UBERON:0001157	74.14	gold quality
apex of heart	UBERON:0002098	73.94	gold quality
jejunal mucosa	UBERON:0000399	73.42	silver quality
rectum	UBERON:0001052	73.21	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	44.41
E-MTAB-6678	yes	23.32
E-ANND-3	yes	14.88
E-MTAB-9067	yes	4.32
E-CURD-112	yes	3.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM, MTF1, SPI1, TBPL1

miRNA regulators (miRDB)

5 targeting ZAP70, 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-185-3P	99.95	67.01	1743
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-3918	96.13	64.65	1300

Literature-anchored findings (GeneRIF, showing 40)

• association of Zap-70 induced by T cell activation in plasma membrane microdomains with GM3 (PMID:11781312)
• Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration. (PMID:11964272)
• ZAP-70, a tyrosine kinase known to be crucial for T cell activation, as a key player in TCR down-modulation and zeta degradation. (PMID:12165490)
• ZAP-70 signaling drives the TCR-dependent reorientation of the microtubule-organizing center (PMID:12387734)
• Expression of ZAP-70 is associated with enhanced signal transduction via the BCR complex, which may contribute to the more aggressive clinical course associated with CLL cells that express nonmutated immunoglobulin receptors. (PMID:12393534)
• VHR, a Vaccinia virus VH1-related dual-specific protein phosphatase, is phosphorylated at Y138 by ZAP-70. (PMID:12447358)
• profiling of gene expression in purified chronic lymphocytic leukemia(CLL)samples from 107 patients showed that ZAP-70 expression is the best discriminator of Ig-mutated and Ig-unmutated CLL (PMID:12595313)
• Impaired ZAP-70 activation is associated with a unique signaling pathway coupling TCR ligation with T cell proliferation. (PMID:12778467)
• ZAP-70 is required for intracellular calcium ion mobilization in response to SDF-1alpha/CXCL12-induced prolonged activation of extracellular signal-related protein kinase in Jurkat T lymphocytes. (PMID:12817019)
• The requirement for ZAP-70 is clearly demonstrated in T cell receptor-induced polarization of the T cell’s microtubule-organizing center, as it moves toward the interface of the T cell and antigen-presenting cell. (PMID:12847255)
• concluded that phosphorylation of ZAP-70 at Ser-520 plays an important role in the correct localization of ZAP-70 and in priming ZAP-70 for its acute recruitment and activation upon antigen receptor ligation (PMID:14560012)
• Lck and ZAP-70 have roles in the interaction of human MUC1 and beta-catenin in activated Jurkat T cells (PMID:14766232)
• The interplay between Syk and ZAP-70 in thymocytes, certain T cells, and B-chronic lymphocytic leukemia cells will modulate the amplitude of antigen-mediated receptor signaling. (PMID:15059847)
• The interdomain B region of ZAP-70 regulates beta 1 integrin activation by the CD3/T cell receptor complex via control of tyrosine phosphorylation of tyrosine residues 171 and 191 in the linker for activation of T cells (LAT) cytoplasmic domain. (PMID:15100278)
• ZAP-70 is expressed by many lymphoma types, correlates with immunoglobulin heavy-chain variable region gene mutational status and can be detected reliably using immunohistochemical methods. (PMID:15133473)
• Essential for T cell receptor signaling and CD8 cell selection. (PMID:15190462)
• three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine (PMID:15292186)
• PD-1 modulation of T-cell function involves inhibition of TCR-mediated phosphorylation of ZAP70 and association with CD3zeta (PMID:15358536)
• ZAP-70 is associated with the mutational status of Ig VH genes in B-CLLs; high levels of ZAP-70 correlated with Binet stages B or C indicating an involvement of ZAP-70 in mechanisms promoting growth of B-CLL cells. (PMID:15370248)
• expression of ZAP-70 in CLL allows for more effective IgM signaling in CLL B cells, a feature that could contribute to the relatively aggressive clinical behavior generally associated with CLL cells that express unmutated IgV(H) (PMID:15514014)
• The ZAP-70 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. (PMID:15759031)
• ZAP-70 is expressed in a subpopulation of tonsillar and splenic normal B-lymphocytes that express an activated phenotype (PMID:15800671)
• murine leukemia model with many similarities to human ZAP-70+ B cell chronic lymphocytic leukemia when human B cells are transplanted into NOD/SCID mice. (PMID:15856008)
• To analyze the expression of Syk tyrosine kinase during the multi step development of human breast carcinoma (PMID:15861514)
• These findings suggest that a general autoinhibitory mechanism employed by RTKs is also used by some cytoplasmic tyrosine kinases, such as ZAP-70. (PMID:15923611)
• ZAP-70 is required for cell survival and signaling in chronic lymphocytic leukemia, and inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling (PMID:15972449)
• ZAP-70 is consistently expressed and phosphorylated in Blin-ALL cells (PMID:15996927)
• oorellation between expression of ZAP-70 and methylation status of a specific CpG site at the intron 1 - exon 2 boundary of the ZAP-70 gene in chronic lymphocytic leukemia. (PMID:16079094)
• Methylation of a highly conserved intronic region of ZAP-70 may be responsible for regulation of expression in normal and chronic lymphocytic leukemia cells. (PMID:16079107)
• results suggest a novel functional role for ZAP 70 in nuclear receptor-driven transactivation in T lymphocytes. (PMID:16096284)
• The difference in the spatio-temporal localization of LCK and ZAP70 proteins following stimulation may eliminate signal crosstalk, and could explain the differentiation of the specific downstream responses of these pathways (PMID:16219325)
• May be a prognostic marker in chronic lymphocytic leukemia. (review) (PMID:16263570)
• In a variety of cell types, Syk is the tyrosine kinase that plays an important role in the activation of Tpl2. (PMID:16291755)
• The aberrant expression of ZAP-70 in more aggressive forms of chronic lymphocytic leukemia requires the chaperoning action of activated heat-shock protein 90, which may be specifically inhibited by the therapeutic strategies discussed in this review. (PMID:16300468)
• results suggest that biological functions attributed to the association of Zap70 with Vav after T cell activation may equally reflect the association of Zap70 with CrkII, and further support a regulatory role for CrkII in TCR-linked signal transduction (PMID:16339550)
• Dexamethasone induces rapid tyrosine-phosphorylation of ZAP-70 in Jurkat cells (PMID:16406604)
• The ZAP-70-TCR-zeta association mediates the activation of PLC-gamma1 leading to T cell responses even in the absence of kinase activation of ZAP-70. (PMID:16412387)
• There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. (PMID:16418492)
• The ZAP70 protein was found expressed in normal pro/pre B cells but not in a significant proportion of normal B cells with mature phenotype. The presence of ZAP-70 in B-ALLs probably reflects their cellular origin. (PMID:16467082)
• Higher cyclin E expression in samples of ZAP 70-positive patients may reflect a larger proliferating compartment in vivo compared to ZAP 70-negative patients with B-cell chronic leukemia. (PMID:16538501)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zap70	ENSDARG00000015752
mus_musculus	Zap70	ENSMUSG00000026117
rattus_norvegicus	Zap70	ENSRNOG00000016995

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), 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 ZAP-70 — P43403 (reviewed: P43403)

Alternative names: 70 kDa zeta-chain associated protein, Syk-related tyrosine kinase

All UniProt accessions (1): P43403

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Also contributes to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the phosphorylated TCR components CD3E and CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).

Subunit / interactions. Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR. Interacts with NFAM1. Interacts with adapter protein SLA; this interaction negatively regulates T-cell receptor signaling. Interacts with FCRL3. Interacts with VAV1. Interacts with CBL; this interaction promotes ubiquitination, internalization and subsequent degradation of CD247/CD3Z. Identified in a complex with CBL and UBE2L3. Interacts with SHB. Interacts with adapter protein SLA2; this interaction negatively regulates T-cell receptor signaling. Interacts with CBLB. Interacts (via SH2 domains) with RHOH; this interaction regulates ZAP70 subcellular localization. Interacts with DEF6. Interacts (ubiquitinated form) with OTUD7B and UBASH3B.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells.

Post-translational modifications. Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319 are essential for ZAP70 positive function on T-lymphocyte activation whereas Tyr-292 has a negative regulatory role. Within the C-terminal kinase domain, Tyr-492 and Tyr-493 are phosphorylated after TCR induction, Tyr-492 playing a negative regulatory role and Tyr-493 a positive. Tyr-493 is dephosphorylated by PTN22. Ubiquitinated in response to T cell activation. Deubiquitinated by OTUD7B.

Disease relevance. Immunodeficiency 48 (IMD48) [MIM:269840] A form of severe immunodeficiency characterized by a selective absence of CD8+ T-cells. The disease is caused by variants affecting the gene represented in this entry. Autoimmune disease, multisystem, infantile-onset, 2 (ADMIO2) [MIM:617006] An autosomal recessive, autoimmune disorder characterized by systemic manifestations including blistering skin disease, uncontrollable bullous pemphigoid, inflammatory colitis, autoimmune hypothyroidism, proteinuria and nephrotic syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphorylation at Tyr-493 in the activation loop. Inhibited by staurosporine.

Domain organisation. Composed of 2 N-terminal SH2 domains and a C-terminal kinase domain. The tandem SH2 domains bind to the doubly phosphorylated tyrosine-based activation motif (ITAM) of CD247/CD3Z and the non-canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH. The interdomain B located between the second SH2 and the kinase domain contains 3 tyrosines (Tyr-292, Tyr-315, Tyr-319) that are phosphorylated following TCR activation. These sites have been implicated in binding to other signaling molecules including CBL or VAV1. Thus, ZAP70 can also function as a scaffold by recruiting additional factors to the stimulated TCR complex.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P43403-1	1	yes
P43403-2	2, TZK
P43403-3	3

RefSeq proteins (3): NP_001070, NP_001365523, NP_997402 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000980	SH2	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR012234	Tyr_kinase_non-rcpt_SYK/ZAP70	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR023420	Kinase_SYK/ZAP-70_inter-SH2_sf	Homologous_superfamily
IPR035838	SYK/ZAP-70_N_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR050198	Non-receptor_tyrosine_kinases	Family

Pfam: PF00017, 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 (110 total): mutagenesis site 26, helix 21, strand 21, sequence variant 13, modified residue 8, turn 7, domain 3, splice variant 3, region of interest 3, binding site 2, chain 1, cross-link 1, active site 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
7SIY	X-RAY DIFFRACTION	1.48
2OQ1	X-RAY DIFFRACTION	1.9
2Y1N	X-RAY DIFFRACTION	2
4XZ0	X-RAY DIFFRACTION	2
2CBL	X-RAY DIFFRACTION	2.1
3ZNI	X-RAY DIFFRACTION	2.21
1U59	X-RAY DIFFRACTION	2.3
5O76	X-RAY DIFFRACTION	2.47
1M61	X-RAY DIFFRACTION	2.5
2OZO	X-RAY DIFFRACTION	2.6
4A4C	X-RAY DIFFRACTION	2.7
4A4B	X-RAY DIFFRACTION	2.79
4XZ1	X-RAY DIFFRACTION	2.8
1FBV	X-RAY DIFFRACTION	2.9
4K2R	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43403-F1	85.91	0.66

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): 461 (proton acceptor)

Ligand- & substrate-binding residues (2): 345–352; 369

Post-translational modifications (9): 248, 289, 292, 315, 319, 492, 493, 603, 544

Mutagenesis-validated functional residues (26):

Position	Phenotype
37	decreases interaction with phosphorylated cd247; when associated with k-190.
131	increased constitutive kinase activity.
133	increased constitutive kinase activity.
141	increased constitutive kinase activity.
144	increased kinase activity after activation by lck.
145	increased kinase activity after activation by lck.
147	increased kinase activity after activation by lck.
190	decreases interaction with phosphorylated cd247; when associated with k-37.
292	induces constitutive tcr stimulation-independent nfat induction.
304	no effect on ubiquitination.
314	increased constitutive kinase activity.
315–319	increases strongly constitutive kinase activity on lat phosphorylation.
315	increased constitutive kinase activity; when associated with f-319.
315	increased constitutive kinase activity; when associated with f-319. about 75% loss of cd247/cd3z-binding in stimulated t
319	increased constitutive kinase activity; when associated with f-315.
319	increased constitutive kinase activity; when associated with f-315. about 80% loss of tcr-induced nfat activation.
327	increases constitutive kinase activity on lat phosphorylation, strongly increases subcellular localization of cd69 at th
362	increases constitutive kinase activity on lat phosphorylation, strongly increases subcellular localization of cd69 at th
461	abolishes kinase activity.
479	abolishes kinase activity.
492	increases kinase activity.
493	impairs kinase activity.
538	no effect on ubiquitination.
544	strongly decreased ubiquitination.
597	increased kinase activity after activation by lck.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse
R-HSA-202433	Generation of second messenger molecules
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer

MSigDB gene sets: 405 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, BIOCARTA_TCRA_PATHWAY, GOBP_THYMIC_T_CELL_SELECTION, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GNF2_ZAP70

GO Biological Process (25): adaptive immune response (GO:0002250), protein phosphorylation (GO:0006468), immune response (GO:0006955), peptidyl-tyrosine phosphorylation (GO:0018108), calcium-mediated signaling (GO:0019722), T cell differentiation (GO:0030217), intracellular signal transduction (GO:0035556), T cell activation (GO:0042110), B cell activation (GO:0042113), beta selection (GO:0043366), positive thymic T cell selection (GO:0045059), negative thymic T cell selection (GO:0045060), positive regulation of T cell differentiation (GO:0045582), positive regulation of alpha-beta T cell differentiation (GO:0046638), positive regulation of alpha-beta T cell proliferation (GO:0046641), positive regulation of calcium-mediated signaling (GO:0050850), T cell receptor signaling pathway (GO:0050852), T cell aggregation (GO:0070489), T cell migration (GO:0072678), immune system process (GO:0002376), leukocyte cell-cell adhesion (GO:0007159), positive regulation of MAPK cascade (GO:0043410), thymic T cell selection (GO:0045061), alpha-beta T cell differentiation (GO:0046632), leukocyte migration (GO:0050900)

GO Molecular Function (9): phosphotyrosine residue binding (GO:0001784), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): immunological synapse (GO:0001772), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), T cell receptor complex (GO:0042101), membrane (GO:0016020), membrane raft (GO:0045121)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCR signaling	2
RHO GTPase cycle	1
Signaling by ALK fusions and activated point mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
lymphocyte activation	2
alpha-beta T cell differentiation	2
thymic T cell selection	2
positive regulation of alpha-beta T cell activation	2
immune response	1
phosphorylation	1
protein modification process	1
immune system process	1
response to stimulus	1
protein phosphorylation	1
peptidyl-tyrosine modification	1
intracellular signaling cassette	1
lymphocyte differentiation	1
T cell activation	1
signal transduction	1
T cell selection	1
positive T cell selection	1
negative T cell selection	1
T cell differentiation	1
regulation of T cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of T cell activation	1
positive regulation of T cell differentiation	1
regulation of alpha-beta T cell differentiation	1
positive regulation of T cell proliferation	1
alpha-beta T cell proliferation	1
regulation of alpha-beta T cell proliferation	1
calcium-mediated signaling	1
regulation of calcium-mediated signaling	1
positive regulation of intracellular signal transduction	1
antigen receptor-mediated signaling pathway	1
lymphocyte aggregation	1
lymphocyte migration	1
biological_process	1
protein phosphorylated amino acid binding	1
protein kinase activity	1
protein tyrosine kinase activity	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

3437 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZAP70	LCP2	Q13094	999
ZAP70	CD247	P20963	998
ZAP70	TYROBP	O43914	994
ZAP70	VAV1	P15498	993
ZAP70	LAT	O43561	989
ZAP70	LCK	P06239	986
ZAP70	GRB2	P29354	984
ZAP70	CBL	P22681	975
ZAP70	SHC1	P29353	945
ZAP70	GRAP2	O75791	926
ZAP70	CD28	P10747	923
ZAP70	CD4	P01730	916
ZAP70	BLNK	Q8WV28	900
ZAP70	UBASH3A	P57075	894
ZAP70	FYN	P06241	892

IntAct

79 interactions, top by confidence:

A	B	Type	Score
ZAP70	CD247	psi-mi:“MI:0915”(physical association)	0.920
ZAP70	CD247	psi-mi:“MI:0914”(association)	0.920
PTPN22	LCK	psi-mi:“MI:0914”(association)	0.780
ZAP70	LCK	psi-mi:“MI:0217”(phosphorylation reaction)	0.700
LCK	ZAP70	psi-mi:“MI:0914”(association)	0.700
LCK	ZAP70	psi-mi:“MI:0915”(physical association)	0.700
EGFR	ZAP70	psi-mi:“MI:0915”(physical association)	0.690
ZAP70	EGFR	psi-mi:“MI:0407”(direct interaction)	0.690

BioGRID (132): ZAP70 (Two-hybrid), ZAP70 (Affinity Capture-Western), ZAP70 (PCA), ZAP70 (Affinity Capture-Luminescence), ZAP70 (Proximity Label-MS), ZAP70 (Affinity Capture-Western), ZAP70 (Affinity Capture-Western), ZAP70 (Reconstituted Complex), ZAP70 (Biochemical Activity), ZAP70 (Co-crystal Structure), ZAP70 (Affinity Capture-Western), ZAP70 (Reconstituted Complex), ZAP70 (Reconstituted Complex), ZAP70 (Affinity Capture-Western), DBNL (Affinity Capture-Western)

ESM2 similar proteins: A8XI74, F1N9Y5, G5ECJ6, O15075, P08487, P08630, P10686, P16885, P19174, P24135, P24604, P35991, P42680, P43403, P43404, P43405, P46108, P46109, P47941, P48025, P51813, P53356, P54936, P87378, Q00655, Q04929, Q06187, Q22070, Q24145, Q45FX5, Q54Y55, Q5U2U2, Q62077, Q62422, Q63768, Q64010, Q64725, Q6P686, Q6TGW5, Q6XJU9

Diamond homologs: A0A8I3NFE2, A6QLK6, B5KFD7, D7PF45, F1N9Y5, O15357, O60880, O88900, P0CE43, P29349, P41242, P41243, P42679, P42686, P43403, P43404, P53356, P97573, Q03160, Q13322, Q13588, Q14449, Q14451, Q1RMW5, Q24708, Q5ICW4, Q5ZL23, Q60760, Q6DCV1, Q6P549, Q6PFT9, Q70E73, Q71S10, Q7Z5R6, Q8BMC3, Q8R5A3, Q92835, Q9BG88, Q9ES52, Q9JLM9

SIGNOR signaling

64 interactions.

A	Effect	B	Mechanism
ZAP70	“up-regulates activity”	LCP2	phosphorylation
ZAP70	“up-regulates activity”	GAB2	phosphorylation
ZAP70	up-regulates	DBNL	phosphorylation
PTCRA	“up-regulates activity”	ZAP70	binding
ZAP70	“up-regulates activity”	MAPK14	phosphorylation
ZAP70	“up-regulates activity”	ZAP70	phosphorylation
PTPN22	down-regulates	ZAP70	dephosphorylation
ZAP70	“up-regulates activity”	LAT	phosphorylation
ZAP70	“up-regulates activity”	MUC1	phosphorylation
PTPN22	“down-regulates activity”	ZAP70	dephosphorylation
LCK	“up-regulates activity”	ZAP70	phosphorylation
LCK	unknown	ZAP70	phosphorylation
RHOH	“up-regulates activity”	ZAP70	binding
STOML2	“up-regulates activity”	ZAP70	binding
DLG1	“up-regulates activity”	ZAP70	phosphorylation
VAV1	“up-regulates activity”	ZAP70	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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	5	75.2×	6e-07
Signaling by SCF-KIT	5	54.0×	2e-06
Constitutive Signaling by Aberrant PI3K in Cancer	7	38.6×	1e-07
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	7	29.4×	4e-07
PIP3 activates AKT signaling	7	20.3×	2e-06
RAF/MAP kinase cascade	6	15.9×	3e-05
Diseases of signal transduction by growth factor receptors and second messengers	6	14.8×	4e-05
Signaling by Receptor Tyrosine Kinases	6	13.5×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	7	48.6×	4e-08
T cell receptor signaling pathway	7	42.5×	5e-08
adaptive immune response	6	20.2×	4e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	18.8×	4e-05
positive regulation of MAPK cascade	5	16.1×	7e-04
negative regulation of gene expression	5	13.8×	1e-03
intracellular signal transduction	8	12.2×	3e-05
protein ubiquitination	5	8.3×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	13
Uncertain significance	217
Likely benign	257
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072344	NM_001079.4(ZAP70):c.475G>T (p.Glu159Ter)	Pathogenic
13253	NM_001079.4(ZAP70):c.1624-11G>A	Pathogenic
13255	NM_001079.4(ZAP70):c.1554C>A (p.Ser518Arg)	Pathogenic
13256	NM_001079.4(ZAP70):c.1510_1522del (p.Lys504fs)	Pathogenic
1390316	NM_001079.4(ZAP70):c.1518C>A (p.Tyr506Ter)	Pathogenic
1394530	NM_001079.4(ZAP70):c.703-1G>A	Pathogenic
1455724	NM_001079.4(ZAP70):c.847C>T (p.Arg283Ter)	Pathogenic
2088832	NM_001079.4(ZAP70):c.1450A>T (p.Lys484Ter)	Pathogenic
2501785	NM_001079.4(ZAP70):c.493del (p.His165fs)	Pathogenic
2697762	NM_001079.4(ZAP70):c.747C>A (p.Cys249Ter)	Pathogenic
2745505	NM_001079.4(ZAP70):c.1120_1135dup (p.Asp379fs)	Pathogenic
3622427	NM_001079.4(ZAP70):c.392G>A (p.Trp131Ter)	Pathogenic
3640729	NM_001079.4(ZAP70):c.1228del (p.Leu410fs)	Pathogenic
3664651	NM_001079.4(ZAP70):c.1258_1261del (p.Gly420fs)	Pathogenic
3674567	NM_001079.4(ZAP70):c.845_846del (p.Arg282fs)	Pathogenic
3721398	NM_001079.4(ZAP70):c.252C>A (p.Cys84Ter)	Pathogenic
3905918	NM_001079.4(ZAP70):c.919_931del (p.Pro307fs)	Pathogenic
418647	NM_001079.4(ZAP70):c.1280del (p.Val427fs)	Pathogenic
4769503	NM_001079.4(ZAP70):c.1244_1253del (p.Glu415fs)	Pathogenic
489150	NM_001079.4(ZAP70):c.117C>A (p.Cys39Ter)	Pathogenic
567226	NM_001079.4(ZAP70):c.1247dup (p.Met416fs)	Pathogenic
659957	NM_001079.4(ZAP70):c.1529_1532dup (p.Ile511fs)	Pathogenic
827753	NM_001079.4(ZAP70):c.283C>T (p.Pro95Ser)	Pathogenic
954252	NM_001079.4(ZAP70):c.261C>G (p.Tyr87Ter)	Pathogenic
1300183	NM_001079.4(ZAP70):c.1065C>T (p.Gly355=)	Likely pathogenic
1325366	NM_001079.4(ZAP70):c.890-1G>C	Likely pathogenic
2767977	NM_001079.4(ZAP70):c.890-1_891del	Likely pathogenic
3587022	NM_001079.4(ZAP70):c.83dup (p.Met29fs)	Likely pathogenic
3666897	NM_001079.4(ZAP70):c.1083-1G>A	Likely pathogenic
3720353	NM_001079.4(ZAP70):c.1690T>C (p.Cys564Arg)	Likely pathogenic

SpliceAI

2885 predictions. Top by Δscore:

Variant	Effect	Δscore
2:97724436:G:GT	donor_gain	1.0000
2:97724436:GAGG:G	donor_loss	1.0000
2:97724438:GG:G	donor_loss	1.0000
2:97724440:T:A	donor_loss	1.0000
2:97725088:CTAG:C	acceptor_loss	1.0000
2:97725089:TA:T	acceptor_loss	1.0000
2:97725090:A:AG	acceptor_gain	1.0000
2:97725090:A:AT	acceptor_loss	1.0000
2:97725090:AG:A	acceptor_gain	1.0000
2:97725090:AGG:A	acceptor_gain	1.0000
2:97725090:AGGGC:A	acceptor_gain	1.0000
2:97725091:G:GG	acceptor_gain	1.0000
2:97725091:GG:G	acceptor_gain	1.0000
2:97725091:GGG:G	acceptor_gain	1.0000
2:97725091:GGGC:G	acceptor_gain	1.0000
2:97725091:GGGCG:G	acceptor_gain	1.0000
2:97725253:G:GG	donor_gain	1.0000
2:97732882:GGCT:G	acceptor_gain	1.0000
2:97733019:CAGGT:C	donor_loss	1.0000
2:97733020:AGGTA:A	donor_loss	1.0000
2:97733022:G:GC	donor_loss	1.0000
2:97733023:T:A	donor_loss	1.0000
2:97734713:G:GG	donor_gain	1.0000
2:97735454:GAG:G	donor_gain	1.0000
2:97735455:AGGTG:A	donor_loss	1.0000
2:97735457:G:C	donor_loss	1.0000
2:97735457:G:GG	donor_gain	1.0000
2:97737466:A:AG	acceptor_gain	1.0000
2:97737467:C:G	acceptor_gain	1.0000
2:97737470:CAGGG:C	acceptor_gain	1.0000

AlphaMissense

4066 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:97725176:T:A	W163R	1.000
2:97725176:T:C	W163R	1.000
2:97725243:G:A	G185D	1.000
2:97725252:T:C	L188P	1.000
2:97732918:T:C	L200P	1.000
2:97733004:T:C	F229L	1.000
2:97733006:T:A	F229L	1.000
2:97733006:T:G	F229L	1.000
2:97733126:T:C	L235P	1.000
2:97734663:G:C	G345R	1.000
2:97734675:T:C	F349L	1.000
2:97734677:T:A	F349L	1.000
2:97734677:T:G	F349L	1.000
2:97734679:G:A	G350D	1.000
2:97734693:G:C	G355R	1.000
2:97734694:G:A	G355D	1.000
2:97734699:T:G	Y357D	1.000
2:97735264:T:A	V366E	1.000
2:97735267:C:A	A367D	1.000
2:97735272:A:C	K369Q	1.000
2:97735272:A:G	K369E	1.000
2:97735274:G:C	K369N	1.000
2:97735274:G:T	K369N	1.000
2:97735326:G:C	A387P	1.000
2:97735374:G:C	G403R	1.000
2:97735375:G:A	G403D	1.000
2:97735402:T:C	L412P	1.000
2:97735405:T:A	V413D	1.000
2:97735410:G:A	E415K	1.000
2:97735411:A:T	E415V	1.000

dbSNP variants (sampled 300 via entrez): RS1000033600 (2:97746424 T>C), RS1000140002 (2:97739702 G>C,T), RS1000252034 (2:97723443 T>C), RS1000321330 (2:97723234 A>G), RS1000340240 (2:97733896 C>G), RS1000436690 (2:97740910 T>G), RS1000618778 (2:97724684 G>A), RS1000653275 (2:97722818 C>A,T), RS1000673530 (2:97735327 C>T), RS1000793176 (2:97729607 C>A), RS1000801197 (2:97731320 C>A), RS1000822290 (2:97712059 A>G), RS1000852710 (2:97747916 A>C,G), RS1000855687 (2:97728021 A>G), RS1000865528 (2:97729737 T>A)

Disease associations

OMIM: gene MIM:176947 | disease phenotypes: MIM:269840, MIM:617006

GenCC curated gene-disease

Disease	Classification	Inheritance
combined immunodeficiency due to ZAP70 deficiency	Definitive	Autosomal recessive
autoimmune disease, multisystem, infantile-onset, 2	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
combined immunodeficiency due to ZAP70 deficiency	Definitive	AR

Mondo (4): combined immunodeficiency due to ZAP70 deficiency (MONDO:0010023), autoimmune disease, multisystem, infantile-onset, 2 (MONDO:0014861), severe combined immunodeficiency (MONDO:0015974), combined immunodeficiency (MONDO:0015131)

Orphanet (3): Combined immunodeficiency due to ZAP70 deficiency (Orphanet:911), Severe combined immunodeficiency (Orphanet:183660), Combined T and B cell immunodeficiency (Orphanet:101972)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0001297	Stroke
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001880	Increased total eosinophil count
HP:0001890	Autoimmune hemolytic anemia
HP:0001973	Autoimmune thrombocytopenia
HP:0002028	Chronic diarrhea
HP:0002090	Pneumonia
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002583	Colitis
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002728	Chronic mucocutaneous candidiasis
HP:0002733	Abnormal lymph node morphology
HP:0002840	Lymphadenitis
HP:0002960	Autoimmunity
HP:0003139	Panhypogammaglobulinemia
HP:0003347	Impaired lymphocyte transformation with phytohemagglutinin
HP:0003593	Infantile onset
HP:0004429	Recurrent viral infections
HP:0004798	Recurrent infection of the gastrointestinal tract
HP:0005390	Recurrent opportunistic infections

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST006630_46	Diastolic blood pressure	6.000000e-13
GCST008103_128	Bipolar disorder	2.000000e-06
GCST008310_6	Cardiac Troponin-T levels	5.000000e-07
GCST010697_1	Cortical surface area (min-P)	6.000000e-12
GCST010698_17	Subcortical volume (min-P)	9.000000e-09
GCST010699_105	Brain morphology (min-P)	2.000000e-11
GCST010700_9	Cortical thickness (MOSTest)	9.000000e-14
GCST010701_54	Cortical surface area (MOSTest)	2.000000e-16
GCST010702_79	Subcortical volume (MOSTest)	5.000000e-09
GCST010703_322	Brain morphology (MOSTest)	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0005043	cardiac troponin T measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C536722	ZAP70 deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2803 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

14 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 70,634 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL274654	ORANTINIB	3	3,596
CHEMBL276711	SEMAXANIB	3	6,180
CHEMBL603469	LESTAURTINIB	3
CHEMBL215152	DEFOSBARASERTIB	2	372
CHEMBL3979920	MIVAVOTINIB	2	103
CHEMBL475251	R-406	2	762
CHEMBL1908397	KW-2449	1	622

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Syk family

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

Ligand	Action	Affinity	Parameter
mivavotinib	Inhibition	7.13	pIC50
aloisine	Inhibition	5.58	pKi
Syk inhibitor II	Inhibition	4.95	pIC50

Binding affinities (BindingDB)

89 measured of 110 human assays (110 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-(3-aminopropyl)-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	1 nM	US-8546370: Compounds and compositions as kinase inhibitors
Staurosporine	KD	1.7 nM
8-[4-(1-methylpiperidin-4-yl)anilino]-6-pyrimidin-5-yl-2H-2,7-naphthyridin-1-one	IC50	2 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(4-ethylpiperazin-1-yl)-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	3 nM	US-8546370: Compounds and compositions as kinase inhibitors
(3R,4R)-3-methoxy-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	IC50	3.93 nM	US-10189849: CDK inhibitors
1-tert-butyl-3-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine	IC50	6 nM
N,2-dimethyl-2-[4-[(8-oxo-3-pyrimidin-5-yl-7H-2,7-naphthyridin-1-yl)amino]phenyl]propanamide	IC50	8 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(5-methoxy-3-pyridinyl)-8-[4-[1-(3-oxobutyl)piperidin-4-yl]anilino]-2H-2,7-naphthyridin-1-one	IC50	8 nM	US-8546370: Compounds and compositions as kinase inhibitors
8-(4-morpholin-4-ylanilino)-6-(2,2,2-trifluoroethylamino)-2H-2,7-naphthyridin-1-one	IC50	24 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(6-methoxypyrazin-2-yl)-8-[3-methyl-4-(oxan-4-yl)anilino]-2H-2,7-naphthyridin-1-one	IC50	31 nM	US-8546370: Compounds and compositions as kinase inhibitors
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide	IC50	33 nM
8-[4-(1-acetylpiperidin-4-yl)anilino]-6-[1-(2-methylpropyl)pyrazol-4-yl]-2H-2,7-naphthyridin-1-one	IC50	44 nM	US-8546370: Compounds and compositions as kinase inhibitors
8-[4-[2-(4-ethylpiperazin-1-yl)ethyl]anilino]-6-(6-methoxypyrazin-2-yl)-2H-2,7-naphthyridin-1-one	IC50	46 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(2-aminopyrimidin-5-yl)-2-methyl-8-[(1-methylpyrazol-4-yl)amino]-2,7-naphthyridin-1-one	IC50	48 nM	US-8546370: Compounds and compositions as kinase inhibitors
8-(4-morpholin-4-ylanilino)-6-phenyl-2H-2,7-naphthyridin-1-one	IC50	58 nM	US-8546370: Compounds and compositions as kinase inhibitors
N,N-dimethyl-4-[(8-oxo-3-pyrimidin-5-yl-7H-2,7-naphthyridin-1-yl)amino]benzamide	IC50	78 nM	US-8546370: Compounds and compositions as kinase inhibitors
3-[(9bR)-5-oxo-1H,2H,3H,5H,9bH-benzo[a]pyrrolizin-9-yl]-1-pyridin-2-ylurea	IC50	78 nM
8-[4-(1-cyclopropylpiperidin-4-yl)-3-methylanilino]-6-pyrimidin-5-yl-2H-2,7-naphthyridin-1-one	IC50	79 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(4-methyl-3-pyridinyl)-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	109 nM	US-8546370: Compounds and compositions as kinase inhibitors
8-[4-(1-methylpiperidin-4-yl)oxyanilino]-6-(4-methyl-1,3-thiazol-2-yl)-2H-2,7-naphthyridin-1-one	IC50	115 nM	US-8546370: Compounds and compositions as kinase inhibitors
5-[(2-aminoethyl)amino]-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	230 nM
6-(5-methoxy-3-pyridinyl)-8-[4-(oxan-4-yl)anilino]-2H-2,7-naphthyridin-1-one	IC50	237 nM	US-8546370: Compounds and compositions as kinase inhibitors
5-bromo-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	277 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-[6-(4-methylimidazol-1-yl)-2-pyridinyl]-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	292 nM	US-8546370: Compounds and compositions as kinase inhibitors
2-methyl-6-[[1-(4-morpholin-4-ylanilino)-8-oxo-7H-2,7-naphthyridin-3-yl]amino]benzenesulfonamide	IC50	324 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(2-aminoethylamino)-8-[3-(trifluoromethyl)anilino]-2H-2,7-naphthyridin-1-one	IC50	398 nM	US-8546370: Compounds and compositions as kinase inhibitors
5-(1-methylpyrazol-4-yl)-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	421 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(2-chlorophenyl)-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	475 nM	US-8546370: Compounds and compositions as kinase inhibitors
(2E)-3-{4-[({8-carbamoyl-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidin-5-yl}amino)methyl]phenyl}prop-2-enoic acid	IC50	690 nM
2-{4-[({8-carbamoyl-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidin-5-yl}amino)methyl]phenyl}acetic acid	IC50	760 nM
4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	KD	1000 nM
7-[(3,5-dimethoxyphenyl)amino]-5-{[(4-fluorophenyl)methyl]amino}imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	1900 nM
5-({[4-(carbamoylmethyl)phenyl]methyl}amino)-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	1900 nM
7-[(3,5-dimethoxyphenyl)amino]-5-[(pyridin-4-ylmethyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	2300 nM
7-[(3,5-dimethoxyphenyl)amino]-5-[(furan-2-ylmethyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	2500 nM
7-[(3,5-dimethoxyphenyl)amino]-5-{[(1S)-1-phenylethyl]amino}imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	3300 nM
5-{[(2,4-difluorophenyl)methyl]amino}-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	3700 nM
7-[(3,5-dimethoxyphenyl)amino]-5-[(2-hydroxyethyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	4300 nM
5-(benzylamino)-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	4300 nM
7-[(3,5-dimethoxyphenyl)amino]-5-[(2-phenylethyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	4800 nM
methyl 4-[({8-carbamoyl-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidin-5-yl}amino)methyl]benzoate	IC50	4800 nM
7-[(3,5-dimethoxyphenyl)amino]-5-{[(2-methoxyphenyl)methyl]amino}imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	5800 nM
7-[(3,5-dimethoxyphenyl)amino]-5-{[(3-methoxyphenyl)methyl]amino}imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	6700 nM
5-amino-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	7100 nM
4-[({8-carbamoyl-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidin-5-yl}amino)methyl]benzoic acid	IC50	8100 nM
7-[(3,5-dimethoxyphenyl)amino]-5-({[4-(hydroxymethyl)phenyl]methyl}amino)imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	8500 nM
5-{[(4-carbamoylphenyl)methyl]amino}-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	8700 nM
5-{[(3,5-difluorophenyl)methyl]amino}-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	9800 nM
5-[(1H-1,3-benzodiazol-2-ylmethyl)amino]-7-[(3,5-dimethoxyphenyl)amino]imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	9800 nM
7-[(3,5-dimethoxyphenyl)amino]-5-{[(4-methoxyphenyl)methyl]amino}imidazo[1,2-a]pyrimidine-8-carboxamide	IC50	11200 nM

ChEMBL bioactivities

290 potent at pChembl≥5 of 340 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3642578
8.96	IC50	1.1	nM	STAUROSPORINE
8.89	IC50	1.3	nM	STAUROSPORINE
8.70	IC50	2	nM	CHEMBL3642585
8.52	IC50	3	nM	CHEMBL3642579
8.48	IC50	3.29	nM	STAUROSPORINE
8.34	IC50	4.6	nM	CHEMBL5416354
8.28	IC50	5.3	nM	CHEMBL3415583
8.28	IC50	5.2	nM	CHEMBL5415461
8.13	IC50	7.35	nM	STAUROSPORINE
8.10	IC50	8	nM	CHEMBL3642588
8.10	IC50	8	nM	CHEMBL3642590
8.10	IC50	8	nM	CHEMBL112346
8.06	IC50	8.63	nM	STAUROSPORINE
8.05	IC50	9	nM	CHEMBL3642579
8.05	IC50	8.9	nM	CHEMBL5404631
8.03	IC50	9.4	nM	CHEMBL5417597
8.00	IC50	10	nM	CHEMBL573483
8.00	IC50	10	nM	CHEMBL575048
7.98	IC50	10.4	nM	CHEMBL5397244
7.96	IC50	11	nM	CHEMBL325912
7.91	IC50	12.4	nM	STAUROSPORINE
7.91	IC50	12.3	nM	STAUROSPORINE
7.85	IC50	14	nM	CHEMBL3262616
7.85	Kd	14	nM	CHEMBL4786316
7.84	IC50	14.6	nM	CHEMBL5414412
7.80	Kd	16	nM	LESTAURTINIB
7.75	IC50	18	nM	CHEMBL3262622
7.68	Kd	21	nM	R-406
7.62	IC50	24	nM	CHEMBL3642587
7.62	IC50	24	nM	MRL-SYKi
7.58	IC50	26	nM	CHEMBL112518
7.55	EC50	28	nM	CHEMBL4582324
7.52	IC50	30	nM	CHEMBL439120
7.52	IC50	30.5	nM	CHEMBL5434338
7.51	IC50	31	nM	CHEMBL3642596
7.51	IC50	31	nM	CHEMBL112172
7.48	IC50	33	nM	CHEMBL3262357
7.42	IC50	38	nM	CHEMBL411163
7.40	IC50	40	nM	CHEMBL573019
7.39	EC50	41	nM	CHEMBL4445994
7.39	IC50	41	nM	CHEMBL459147
7.38	IC50	42	nM	R-406
7.38	EC50	42	nM	CHEMBL4577049
7.36	IC50	44	nM	CHEMBL3642583
7.36	Kd	44	nM	STAUROSPORINE
7.35	IC50	44.8	nM	CHEMBL4870513
7.34	IC50	46	nM	CHEMBL3642595
7.34	IC50	46	nM	CHEMBL420672
7.33	IC50	47	nM	CHEMBL3262620

PubChem BioAssay actives

312 with measured affinity, of 1509 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
(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	1762564: Inhibition of N-terminal GST-fused human recombinant full length ZAP70 (1 to 619 residues) expressed in baculovirus-infected Sf21 cells using FAM-22 peptide as substrate preincubated with enzyme for 10 mins followed by substrate addition for 30 mins in presence of ATP by caliper mobility shift assay	ic50	0.0011	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0046	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-methoxy-4-[4-(oxetan-3-yl)piperazin-1-yl]anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0052	uM
5-[[(1R,2S)-2-aminocyclohexyl]amino]-3-[(4,6-dimethyl-2-pyridinyl)amino]pyridine-2-carboxamide	1199534: Inhibition of GST-fused Zap70 (unknown origin) expressed in insect SF9 cells using biotin-EQEDEPEGDYFEWLE-CONH2 as substrate preincubated for 10 mins followed by substrate/ATP addition measured after 45 mins by TR-FRET assay	ic50	0.0053	uM
4-[6-[(3S)-3-ethylpiperazin-1-yl]-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0080	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[4-(4-hydroxypiperidin-1-yl)-3-methoxyanilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0089	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-(3-ethoxy-4-morpholin-4-ylanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0094	uM
4-[4-[[5-chloro-4-(2-propylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-N-methylpiperazine-1-carboxamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0100	uM
2-[[5-bromo-2-(2,3-dihydro-1H-inden-4-ylamino)pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0100	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-methoxy-4-(4-methyl-1,4-diazepan-1-yl)anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0104	uM
4-[6-[(3S)-3-methylpiperazin-1-yl]-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0110	uM
7-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-4-ylamino)-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0140	uM
5-[[4-[4-[(dimethylamino)methyl]pyrazol-1-yl]pyrimidin-2-yl]amino]-N,1-dimethylindazole-3-carboxamide	1681029: Binding affinity to ZAP70 (unknown origin)	kd	0.0140	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-(3-methoxy-4-morpholin-4-ylanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0146	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	508138: Binding affinity to ZAP70	kd	0.0160	uM
6-[[(3R,4R)-3-aminooxan-4-yl]amino]-8-[(2-methylindazol-4-yl)amino]-2H-2,7-naphthyridin-1-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0180	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	624744: Binding constant for ZAP70 kinase domain	kd	0.0210	uM
4-[6-(3-methylpiperazin-1-yl)-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0260	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]-3-methylphenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0280	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-phosphonooxyphenyl)propanoyl]amino]-4-oxobutanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-3-(4-phosphonooxyphenyl)propanoyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]butanedioic acid	221985: Inhibition of binding to human ZAP-70 SH2 domain	ic50	0.0300	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-(hydroxymethyl)-4-morpholin-4-ylanilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0305	uM
4-[6-(1,4-diazepan-1-yl)-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0310	uM
7-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[(3-methyl-1H-indol-7-yl)amino]-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0330	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-amino-4-oxobutanoyl]amino]-5-amino-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-3-(4-phosphonooxyphenyl)propanoyl]amino]-4-amino-4-oxobutanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-4-amino-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-1-oxo-3-(4-phosphonooxyphenyl)propan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	220421: Binding affinity against SH2 domain of Zeta-chain (TCR) associated protein kinase 70 kDa	ic50	0.0380	uM
4-[4-[[5-chloro-4-(2-propylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-N,N-dimethylpiperazine-1-carboxamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0400	uM
5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-(3,5-dimethoxyanilino)-2-phenylimidazo[1,2-c]pyrimidine-8-carboxamide	389369: Inhibition of human ZAP70 expressed in Sf9 cells	ic50	0.0410	uM
N-[3-chloro-4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]phenyl]-1-[1-(3-cyano-3-methylbutanoyl)piperidin-4-yl]-5-fluoroindazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0410	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[3-methyl-4-(pyrazolo[1,5-a]pyridine-3-carbonylamino)phenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0420	uM
5-[[3-[(2-chloroacetyl)amino]phenyl]methylamino]-7-(3,5-dimethoxyanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0448	uM
4-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0460	uM
(E)-3-[4-[[[8-carbamoyl-7-(3,5-dimethoxyanilino)imidazo[1,2-c]pyrimidin-5-yl]amino]methyl]phenyl]prop-2-enoic acid	1798683: Intracellular ZAP-70 Kinase Inhibition Assay from Article 10.1016/j.bmc.2008.10.070: “Structure-activity relationship studies of 5-benzylaminoimidazo[1,2-c]pyrimidine-8-carboxamide derivatives as potent, highly selective ZAP-70 kinase inhibitors.”	ic50	0.0470	uM
7-[[(3R,4R)-3-aminooxan-4-yl]amino]-5-[(3-methyl-1H-indol-7-yl)amino]-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0470	uM
7-(3,5-dimethoxyanilino)-5-[[4-fluoro-3-(prop-2-enoylamino)phenyl]methylamino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0475	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[3-chloro-4-(pyrazolo[1,5-a]pyridine-3-carbonylamino)phenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0490	uM
2-[[5-chloro-2-[4-[3-(dimethylamino)-2,2-dimethylpropoxy]-2-methoxyanilino]pyrimidin-4-yl]amino]-N-propan-2-ylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0500	uM
4-(6-piperazin-1-yl-3-pyridinyl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0540	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[3-chloro-4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]phenyl]-5-fluoroindazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0560	uM
7-(3,5-dimethoxyanilino)-5-[[2-(prop-2-enoylamino)-4-pyridinyl]methylamino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0583	uM
2-[[(1R,2S)-2-aminocyclohexyl]amino]-4-[3-(triazol-2-yl)anilino]pyrimidine-5-carboxamide	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0600	uM
3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-7-ylamino)-1,2,4-triazine-6-carboxamide	1199675: Competitive binding affinity to human ZAP70	kd	0.0650	uM
2-[[5-bromo-2-[3-(dimethylamino)-2-methylanilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0700	uM
5-[[4-[4-[(dimethylamino)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-N,1-dimethylindazole-3-carboxamide	1681029: Binding affinity to ZAP70 (unknown origin)	kd	0.0730	uM
7-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[3-(triazol-2-yl)anilino]-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0740	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-(4-morpholin-4-ylanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0748	uM
6-[[(1R,2S)-2-aminocyclohexyl]amino]-7-fluoro-4-(1-methylpyrazol-4-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one	1330028: Inhibition of human full length N-terminal GST-tagged ZAP-70 (1 to 619 residues) expressed in baculovirus expression system using ULight peptide as substrate after 1 hr in presence of ATP by TR-FRET assay	ic50	0.0750	uM
2-[[5-bromo-2-[2-methoxy-4-(2-methylimidazol-1-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0800	uM
6-[[(1R,2S)-2-aminocyclohexyl]amino]-8-[(3-methyl-1H-indol-7-yl)amino]-2H-2,7-naphthyridin-1-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0810	uM
ethyl (E)-3-[4-[[[8-carbamoyl-7-(3,5-dimethoxyanilino)imidazo[1,2-c]pyrimidin-5-yl]amino]methyl]phenyl]prop-2-enoate	1798683: Intracellular ZAP-70 Kinase Inhibition Assay from Article 10.1016/j.bmc.2008.10.070: “Structure-activity relationship studies of 5-benzylaminoimidazo[1,2-c]pyrimidine-8-carboxamide derivatives as potent, highly selective ZAP-70 kinase inhibitors.”	ic50	0.0880	uM
1-[1-(3-cyano-3-methylbutanoyl)piperidin-4-yl]-N-[3-methyl-4-(pyrazolo[1,5-a]pyridine-3-carbonylamino)phenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0880	uM
1-[4-[[5-chloro-4-(2-propylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperidine-4-carboxamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0900	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases mutagenesis, affects methylation, decreases expression	4
(+)-JQ1 compound	decreases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
Nickel	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
GSK-J4	increases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	decreases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
bisperoxovanadium	increases expression, affects reaction	1
ON 01910	decreases phosphorylation	1
Dasatinib	increases response to substance	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Air Pollutants	increases expression, increases abundance	1
Allergens	affects cotreatment, increases expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Camptothecin	decreases response to substance	1
Polycyclic Aromatic Hydrocarbons	increases activity	1
Valproic Acid	increases methylation	1
Vanadium	decreases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

451 unique, capped per target: 448 binding, 2 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006346	Binding	Inhibition of Tel-fused ZAP70 kinase-mediated mouse BaF3 cell proliferation	Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. — Proc Natl Acad Sci U S A
CHEMBL4424915	ADMET	Inhibition of human full-length C-terminal His6-tagged ZAP70 expressed in baculovirus infected Sf21 insect cells using Poly (Glu4-Tyr) (4:1) as substrate	Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952. — Bioorg Med Chem Lett
CHEMBL823525	Functional	Antagonistic activity at 100 uMolar concentration to the SH2 domain of ZAP-70 protein.	Solid phase synthesis of a biased mini tetrapeptoid-library for the discovery of monodentate ITAM mimics as ZAP-70 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6430	P116.cl39	Cancer cell line	Male
CVCL_B2LM	Abcam HeLa ZAP70 KO	Cancer cell line	Female
CVCL_B7VC	Abcam Jurkat ZAP70 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT02737384	PHASE2	TERMINATED	Hematopoietic Stem Cells Transplantation in Children With Combined Immunodeficiency (CID)
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID