YES1

gene
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Also known as Yesc-yesHsT441

Summary

YES1 (YES proto-oncogene 1, Src family tyrosine kinase, HGNC:12841) is a protein-coding gene on chromosome 18p11.32, encoding Tyrosine-protein kinase Yes (P07947). Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation.

This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22.

Source: NCBI Gene 7525 — RefSeq curated summary.

At a glance

  • GWAS associations: 13
  • Clinical variants (ClinVar): 73 total
  • Druggable target: yes — 66 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_005433

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:12841
Approved symbolYES1
NameYES proto-oncogene 1, Src family tyrosine kinase
Location18p11.32
Locus typegene with protein product
StatusApproved
AliasesYes, c-yes, HsT441
Ensembl geneENSG00000176105
Ensembl biotypeprotein_coding
OMIM164880
Entrez7525

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 22 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000314574, ENST00000577611, ENST00000577961, ENST00000581960, ENST00000584307, ENST00000892684, ENST00000892685, ENST00000892686, ENST00000892687, ENST00000892688, ENST00000892689, ENST00000925072, ENST00000925073, ENST00000925074, ENST00000925075, ENST00000925076, ENST00000925077, ENST00000925078, ENST00000925079, ENST00000925080, ENST00000945836, ENST00000945837, ENST00000945838, ENST00000945839

RefSeq mRNA: 1 — MANE Select: NM_005433 NM_005433

CCDS: CCDS11824

Canonical transcript exons

ENST00000314574 — 12 exons

ExonStartEnd
ENSE00001214226732834732965
ENSE00001214236736808736961
ENSE00001214245739735739811
ENSE00001214251742918743097
ENSE00001214256743260743415
ENSE00001214274745948746051
ENSE00001214283747920748018
ENSE00001214293751705751804
ENSE00001542048721588724632
ENSE00001665786745708745857
ENSE00002704426812114812242
ENSE00003596873756557756835

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.8243 / max 343.0358, expressed in 1669 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter IDTPM avgSamples expressed
17095229.68341659
1709534.27161411
1709540.5509267
1709550.3185146

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
secondary oocyteCL:000065598.57gold quality
oocyteCL:000002398.42gold quality
jejunal mucosaUBERON:000039997.17gold quality
parotid glandUBERON:000183196.75gold quality
buccal mucosa cellCL:000233696.73gold quality
visceral pleuraUBERON:000240196.55gold quality
gingival epitheliumUBERON:000194996.47gold quality
esophagus squamous epitheliumUBERON:000692096.43gold quality
parietal pleuraUBERON:000240096.18gold quality
pleuraUBERON:000097796.12gold quality
endothelial cellCL:000011596.09gold quality
gingivaUBERON:000182896.01gold quality
squamous epitheliumUBERON:000691496.00gold quality
corpus epididymisUBERON:000435995.69gold quality
mammary ductUBERON:000176595.46gold quality
oral cavityUBERON:000016795.37gold quality
skin of hipUBERON:000155495.26gold quality
epithelium of mammary glandUBERON:000324495.24gold quality
lower lobe of lungUBERON:000894995.24gold quality
nephron tubuleUBERON:000123195.18gold quality
mucosa of sigmoid colonUBERON:000499395.12gold quality
choroid plexus epitheliumUBERON:000391195.03gold quality
amniotic fluidUBERON:000017394.91gold quality
tibiaUBERON:000097994.74gold quality
epithelium of esophagusUBERON:000197694.71gold quality
renal glomerulusUBERON:000007494.70gold quality
cartilage tissueUBERON:000241894.65gold quality
colonic mucosaUBERON:000031794.54gold quality
periodontal ligamentUBERON:000826694.50gold quality
metanephric glomerulusUBERON:000473694.48gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-ANND-3yes9.16
E-MTAB-7381no58.50
E-CURD-112no3.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, NANOG

miRNA regulators (miRDB)

190 targeting YES1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-5692A100.0074.406850
HSA-MIR-340-5P100.0072.504437
HSA-MIR-3163100.0077.238605
HSA-MIR-30A-5P100.0076.313233
HSA-MIR-30B-5P100.0076.293248
HSA-MIR-30C-5P100.0076.293248
HSA-MIR-30D-5P100.0076.323233
HSA-MIR-30E-5P100.0076.323242
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-366299.9973.825684
HSA-MIR-371B-5P99.9975.344759
HSA-MIR-569699.9872.364487
HSA-MIR-477599.9875.006394
HSA-MIR-1213699.9872.815713
HSA-MIR-520D-5P99.9873.344883
HSA-MIR-524-5P99.9873.434882
HSA-MIR-548P99.9872.253784
HSA-MIR-373-5P99.9875.364753
HSA-MIR-616-5P99.9875.584775
HSA-MIR-314899.9775.066478
HSA-MIR-60799.9773.625593
HSA-MIR-50799.9770.111915
HSA-MIR-211099.9666.681930
HSA-MIR-548AJ-3P99.9673.385345
HSA-MIR-548X-3P99.9673.385345
HSA-MIR-146A-5P99.9668.93988
HSA-MIR-146B-5P99.9669.13977
HSA-MIR-4666A-3P99.9671.713434
HSA-MIR-570-3P99.9672.414910
HSA-MIR-590-3P99.9674.346478

Literature-anchored findings (GeneRIF, showing 40)

  • cAMP activates while Ca(2+) inhibits human sperm c-yes kinase activity (PMID:12080032)
  • QM binds to c-yes at the SH3 domain in tumor cell lines (PMID:12138090)
  • This review summarizes the potential functions of c-Yes and its ability to modulate signals that are distinct from c-Src. (PMID:12456296)
  • Src family kinase Yes triggers hyperosmotic activation of the epidermal growth factor receptor and CD95 (PMID:15039424)
  • activation of c-Yes is important for maintaining embryonic stem cells in an undifferentiated state (PMID:15148312)
  • c-Yes 3’-UTR contains at least three newly identified adenine/uridine-rich elements (AREs) which are bound specifically by ARE-binding proteins HuR and AUF1. (PMID:16289864)
  • Vascular endothelial growth factor (VEGF)-induced cell migration is significantly decreased in Yes-deficient retinal microvascular endothelial cells. (PMID:16400523)
  • NFAT1, a transcription factor connected with breast cancer metastasis, is activated by Wnt-5a through a Ca2+ signaling pathway in human breast epithelial cells which was simultaneously counteracted by a Wnt-5a-induced Yes/Cdc42 signaling pathway. (PMID:16880514)
  • activation of the protooncogene product c-Yes may play a significant role in the malignant transformation of hepatocytes (PMID:17007035)
  • The results were confirmed at the level of mRNA and protein, and suggested that four genes (OPCML, RNASE1, YES1 and ACK1) could play a key role in the tumorigenesis and metastasis of gastric cancer. (PMID:17109515)
  • Nucleus-located c-Yes may be a useful marker to detect early-stage hepatocellular carcinoma. (PMID:17143518)
  • Amyloid aggregation by an SH3 domain from the Src family. (PMID:17418139)
  • Thus, these results suggest that endogenous c-Src, c-Yes, and Lyn are differentially activated through Cdc2 activation during M phase. (PMID:17692281)
  • c-Yes induction results in increased colorectal carcinoma cell motility but did not promote proliferation. In later stages of colorectal carcinogenesis, elevations in c-Yes levels/activity may promote cancer spread & metastasis rather than tumor growth. (PMID:17898870)
  • Binding of CD95 Ligand to CD95 on glioblastoma cells recruit Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. (PMID:18328427)
  • These results suggest that SFK trafficking is specified by the palmitoylation state in the SH4 domain. (PMID:19258394)
  • Cloning of the complete coding sequence of the cDNA of the Csk and Yes tyrosine kinases genes of the human lymphocytes and retina have been carried out. (PMID:19757166)
  • Data show that found that IFIH1, a susceptibility gene of type 1 diabetes, interacts with YES1, which plays a role in glucose transport. (PMID:19797678)
  • Study identified the previously reported pathogenic mutation of NTRK3 in a KRAS/BRAF wild-type tumor and 2 somatic mutations in the Src family of kinases (YES1 and LYN) that would be expected to cause structural changes. (PMID:19893451)
  • Both YES and STAT1 were verified as direct miR-145 targets (PMID:20098684)
  • c-Yes was expressed in malignant melanoma, and squamous cell carcinoma type skin neoplasms. (PMID:20796316)
  • Yes-associated protein may play important roles in different pathways in distinct lung tumor subtypes. (PMID:21190720)
  • c-Yes regulates specific oncogenic signalling pathways important for colon cancer progression that is not shared with c-Src. (PMID:21390316)
  • Functional activation of Src family kinase yes protein is essential for the enhanced malignant properties of human melanoma cells expressing ganglioside GD3. (PMID:21454696)
  • Taken together, our findings demonstrate that Yes and Lyn phosphorylate EGFR at Y1101, which influences EGFR nuclear translocation in this model of cetuximab resistance. (PMID:22430206)
  • study concludes that Yes is a central mediator for malignant mesothelioma cell growth that is not shared with other Src family kinases such as c-Src (PMID:22948717)
  • we identified CRKL/YES as critical interrelated pathways necessary for rhabdomyosarcoma cell growth and survival and suggest a potential therapeutic role of SRC family kinase inhibition in the treatment of rhabdomyosarcoma. (PMID:23318429)
  • Expression of HPV type 16 E7 resulted in increase in Src and Yes proteins level, but did not alter the level of Fyn. (PMID:23497302)
  • YES1 and YAP transcript levels were higher in liver metastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. (PMID:24323901)
  • YES kinase as a proximal glucose-specific signal in the Cdc42-signaling cascade. (PMID:24610809)
  • Results demonstrate a unique role for Yes in phosphorylation of FAK and in promoting PCa metastasis. Therefore, phosphorylated FAK Y861 and increased Yes expression may be predictive markers for PCa metastasis. (PMID:25868388)
  • findings indicate that miR-203 induces the apoptosis of KB cells by directly targeting Yes-1, suggesting its application in anti-cancer therapeutics (PMID:25910964)
  • Increased YES/SFK activation might serve as a clinical biomarker for predicting tumor resistance to IGF-1R inhibition. (PMID:25925378)
  • Up-regulation of miR-210 inhibits hepatocellular carcinoma cell proliferation. Yes1 is a target of miR-210 and affects cell proliferation in HCC. (PMID:26676187)
  • Our results suggest that H19 functions as a competitive endogenous RNA (ceRNA) by acting as a sink for miR-17-5p, revealing a potential ceRNA regulatory network involving H19 and miR-17-5p with a role in the modulation of YES1 expression (PMID:27093644)
  • c-Yes plays an important role in migration and invasion of epithelial ovarian cancer. (PMID:27289010)
  • Study on the role of miR-140-5p in inhibiting tumorigenesis in gastric cancer thru targeting YES proto-oncogene 1(YES1). (PMID:28818100)
  • The downregulation of miR-199a contributes to paclitaxel (PTX) resistance in prostate cancer. YES1 mediates the regulation of miR-199a in prostate cancer PTX resistance. (PMID:29204706)
  • findings identify acquired amplification of YES1 as a recurrent and targetable mechanism of resistance to EGFR inhibition in EGFR-mutant lung cancers and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance. (PMID:29875142)
  • YES1 is essential for NSCLC carcinogenesis. YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. (PMID:31166114)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_rerioyes1ENSDARG00000005941
mus_musculusYes1ENSMUSG00000014932
rattus_norvegicusYes1ENSRNOG00000037227

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ITK (ENSG00000113263), ZAP70 (ENSG00000115085), PTK2B (ENSG00000120899), SRMS (ENSG00000125508), TEC (ENSG00000135605), BLK (ENSG00000136573), ABL2 (ENSG00000143322), FER (ENSG00000151422), JAK1 (ENSG00000162434), SYK (ENSG00000165025), PTK2 (ENSG00000169398), TNK1 (ENSG00000174292), FES (ENSG00000182511), LCK (ENSG00000182866), SRC (ENSG00000197122), LYN (ENSG00000254087)

Protein

Protein identifiers

Tyrosine-protein kinase YesP07947 (reviewed: P07947)

Alternative names: Proto-oncogene c-Yes, p61-Yes

All UniProt accessions (2): P07947, J3QRU1

UniProt curated annotations — full annotation on UniProt →

Function. Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGFR, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin-dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis. Catalyzes phosphorylation of organic cation transporter OCT2 which induces its transport activity.

Subunit / interactions. Interacts with YAP1 and CSF1R. Interacts with CTNND1; this interaction allows YES1-mediated activation of FYN and FER and subsequent phosphorylation of CTNND1. Interacts with FASLG. Interacts with IL6ST/gp130. Interacts with SCRIB, when YES1 is in a closed conformation; the interaction facilitates YES1 autophosphorylation.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cytosol. Cell junction.

Tissue specificity. Expressed in the epithelial cells of renal proximal tubules and stomach as well as hematopoietic cells in the bone marrow and spleen in the fetal tissues. In adult, expressed in epithelial cells of the renal proximal tubules and present in keratinocytes in the basal epidermal layer of epidermis.

Post-translational modifications. Phosphorylated. Phosphorylation by CSK on the C-terminal tail maintains the enzyme in an inactive state. Autophosphorylation at Tyr-426 maintains enzyme activity by blocking CSK-mediated inhibition. Palmitoylation at Cys-3 promotes membrane localization.

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

RefSeq proteins (1): NP_005424* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000719Prot_kinase_domDomain
IPR000980SH2Domain
IPR001245Ser-Thr/Tyr_kinase_cat_domDomain
IPR001452SH3_domainDomain
IPR008266Tyr_kinase_ASActive_site
IPR011009Kinase-like_dom_sfHomologous_superfamily
IPR017441Protein_kinase_ATP_BSBinding_site
IPR020635Tyr_kinase_cat_domDomain
IPR035751Yes_SH3Domain
IPR036028SH3-like_dom_sfHomologous_superfamily
IPR036860SH2_dom_sfHomologous_superfamily
IPR050198Non-receptor_tyrosine_kinasesFamily

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.

SubstrateKm (mM)Measurements
ATP0.014–17.6412
[KDSRC KINASE]-L-TYROSINE0.0057–0.2412
POLY(GLU4-TYR)0.018–0.65910
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO0.0571
S1 PEPTIDE0.0371
EEEEY0

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (30 total): modified residue 8, strand 5, domain 3, lipid moiety-binding region 2, sequence variant 2, binding site 2, initiator methionine 1, chain 1, mutagenesis site 1, turn 1, helix 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDBMethodResolution (Å)
2HDAX-RAY DIFFRACTION1.9

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P07947-F183.190.67

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): 396 (proton acceptor)

Ligand- & substrate-binding residues (2): 283–291; 305

Post-translational modifications (10): 21, 32, 40, 336, 345, 426, 446, 537, 2, 3

Mutagenesis-validated functional residues (1):

PositionPhenotype
426about 50% loss of csk-mediated inhibition.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

IDPathway
R-HSA-1227986Signaling by ERBB2
R-HSA-1433557Signaling by SCF-KIT
R-HSA-1433559Regulation of KIT signaling
R-HSA-2029481FCGR activation
R-HSA-210990PECAM1 interactions
R-HSA-2682334EPH-Ephrin signaling
R-HSA-389356Co-stimulation by CD28
R-HSA-389513Co-inhibition by CTLA4
R-HSA-3928662EPHB-mediated forward signaling
R-HSA-3928663EPHA-mediated growth cone collapse
R-HSA-3928665EPH-ephrin mediated repulsion of cells
R-HSA-8940973RUNX2 regulates osteoblast differentiation
R-HSA-912631Regulation of signaling by CBL
R-HSA-9664323FCGR3A-mediated IL10 synthesis
R-HSA-9664422FCGR3A-mediated phagocytosis
R-HSA-9670439Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants
R-HSA-9680350Signaling by CSF1 (M-CSF) in myeloid cells

MSigDB gene sets: 388 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CARBOHYDRATE_TRANSPORT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, DORSAM_HOXA9_TARGETS_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, TGCACTT_MIR519C_MIR519B_MIR519A, HOFMANN_CELL_LYMPHOMA_UP, PID_NETRIN_PATHWAY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (15): negative regulation of inflammatory response to antigenic stimulus (GO:0002862), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), regulation of D-glucose transmembrane transport (GO:0010827), cell differentiation (GO:0030154), T cell costimulation (GO:0031295), cellular response to platelet-derived growth factor stimulus (GO:0036120), protein modification process (GO:0036211), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), regulation of vascular permeability (GO:0043114), positive regulation of transcription by RNA polymerase II (GO:0045944), ephrin receptor signaling pathway (GO:0048013), leukocyte migration (GO:0050900), cellular response to retinoic acid (GO:0071300), cellular response to transforming growth factor beta stimulus (GO:0071560), protein phosphorylation (GO:0006468)

GO Molecular Function (12): 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), enzyme binding (GO:0019899), transmembrane transporter binding (GO:0044325), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (11): Golgi apparatus (GO:0005794), centrosome (GO:0005813), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), focal adhesion (GO:0005925), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-13 pathways:

CategoryPathways
EPH-Ephrin signaling3
Signaling by Receptor Tyrosine Kinases2
Regulation of T cell activation by CD28 family2
Signaling by SCF-KIT1
Fcgamma receptor (FCGR) dependent phagocytosis1
Cell surface interactions at the vascular wall1
Axon guidance1
RUNX2 regulates bone development1
Interleukin-3, Interleukin-5 and GM-CSF signaling1
Anti-inflammatory response favouring Leishmania parasite infection1
Leishmania phagocytosis1
Signaling by KIT in disease1
Cytokine Signaling in Immune system1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
protein binding3
cellular anatomical structure3
cellular response to growth factor stimulus2
cytoplasm2
inflammatory response to antigenic stimulus1
regulation of inflammatory response to antigenic stimulus1
negative regulation of inflammatory response1
negative regulation of immune response1
enzyme-linked receptor protein signaling pathway1
regulation of transmembrane transport1
D-glucose transmembrane transport1
cellular developmental process1
lymphocyte costimulation1
positive regulation of T cell activation1
response to platelet-derived growth factor1
protein metabolic process1
macromolecule modification1
Fc receptor mediated stimulatory signaling pathway1
phagocytosis1
Fc-gamma receptor signaling pathway1
vascular process in circulatory system1
blood circulation1
regulation of biological quality1
regulation of transcription by RNA polymerase II1
transcription by RNA polymerase II1
positive regulation of DNA-templated transcription1
cell surface receptor protein tyrosine kinase signaling pathway1
immune system process1
cell migration1
response to retinoic acid1
cellular response to lipid1
cellular response to oxygen-containing compound1
response to transforming growth factor beta1
phosphorylation1
protein modification process1
protein phosphorylated amino acid binding1
protein kinase activity1
protein tyrosine kinase activity1
adenyl ribonucleotide binding1
purine ribonucleoside triphosphate binding1

Protein interactions and networks

STRING

2582 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
YES1YAP1P46937936
YES1TBX5Q99593756
YES1TYMSP04818752
YES1ADRA2CP18825691
YES1EGFRP00533612
YES1CTNNB1P35222566
YES1GRB2P29354562
YES1OCLNQ16625543
YES1TJP1Q07157527
YES1SHC1P29353509
YES1CDC42P21181501
YES1CAV1Q03135482
YES1PTPN13Q12923475
YES1MAP2K1Q02750456
YES1MAP2K2P36507447

IntAct

447 interactions, top by confidence:

ABTypeScore
YES1SOCS3psi-mi:“MI:0915”(physical association)0.720
PTK2YES1psi-mi:“MI:0915”(physical association)0.720
YES1FXR2psi-mi:“MI:0915”(physical association)0.720
YES1TRAF2psi-mi:“MI:0915”(physical association)0.720
YES1ZBTB8Apsi-mi:“MI:0915”(physical association)0.720
YES1SSBP3psi-mi:“MI:0915”(physical association)0.720
YES1THAP1psi-mi:“MI:0915”(physical association)0.720
YES1TRAF6psi-mi:“MI:0915”(physical association)0.720
SSBP3YES1psi-mi:“MI:0915”(physical association)0.720
TRAF6YES1psi-mi:“MI:0915”(physical association)0.720
SOCS3YES1psi-mi:“MI:0915”(physical association)0.720
THAP1YES1psi-mi:“MI:0915”(physical association)0.720

BioGRID (513): SPRR2A (Reconstituted Complex), YES1 (Two-hybrid), YES1 (Two-hybrid), YES1 (Two-hybrid), SOCS3 (Two-hybrid), FXR2 (Two-hybrid), SSBP3 (Two-hybrid), THAP1 (Two-hybrid), NIF3L1 (Two-hybrid), C1orf94 (Two-hybrid), FUNDC1 (Two-hybrid), ZBTB8A (Two-hybrid), YES1 (Affinity Capture-MS), YES1 (Affinity Capture-MS), YES1 (Affinity Capture-MS)

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

18 interactions.

AEffectBMechanism
YES1down-regulatesCDK4phosphorylation
YES1“up-regulates activity”YES1phosphorylation
YES1“up-regulates activity”WBP2phosphorylation
YES1“down-regulates activity”YY1phosphorylation
YES1“up-regulates quantity by stabilization”SOCS1phosphorylation
AXL“up-regulates activity”YES1phosphorylation
EPHA2“up-regulates activity”YES1phosphorylation
YES1“up-regulates activity”YAP1phosphorylation
YES1“up-regulates activity”WWTR1phosphorylation
IL6ST“up-regulates activity”YES1phosphorylation
YES1“up-regulates activity”ANXA2phosphorylation
YES1“up-regulates activity”POU2F2phosphorylation
RPL10down-regulatesYES1binding
YES1“up-regulates activity”GLO1phosphorylation
YES1“down-regulates activity”SOCS1phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 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:

PathwayPartnersFoldFDR
Signaling by PTK6533.2×1e-04
Signaling by Non-Receptor Tyrosine Kinases533.2×1e-04
Downstream signal transduction523.2×5e-04
Signaling by BRAF and RAF1 fusions510.4×5e-03
Extra-nuclear estrogen signaling510.4×5e-03
VEGFA-VEGFR2 Pathway610.2×3e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling67.1×7e-03
PIP3 activates AKT signaling86.5×3e-03

GO biological processes:

GO termPartnersFoldFDR
regulation of cell growth612.1×2e-03
cell surface receptor protein tyrosine kinase signaling pathway711.1×2e-03
T cell receptor signaling pathway79.7×2e-03
regulation of apoptotic process118.3×8e-05
negative regulation of gene expression95.7×4e-03
cell migration105.6×2e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance56
Likely benign3
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2531 predictions. Top by Δscore:

VariantEffectΔscore
18:724630:TAC:Tacceptor_gain1.0000
18:736802:TTTTA:Tdonor_loss1.0000
18:736803:TTTA:Tdonor_loss1.0000
18:736804:TTACC:Tdonor_loss1.0000
18:736805:TACC:Tdonor_loss1.0000
18:736806:A:Tdonor_loss1.0000
18:736807:CCTTG:Cdonor_loss1.0000
18:736958:CAAT:Cacceptor_gain1.0000
18:736960:AT:Aacceptor_gain1.0000
18:736962:C:CCacceptor_gain1.0000
18:736963:T:Cacceptor_gain1.0000
18:736963:T:TCacceptor_gain1.0000
18:739731:ATAC:Adonor_loss1.0000
18:739732:TAC:Tdonor_loss1.0000
18:739733:A:ATdonor_loss1.0000
18:739734:CC:Cdonor_loss1.0000
18:739813:T:Cacceptor_loss1.0000
18:739835:A:Cacceptor_gain1.0000
18:742915:TACCT:Tdonor_loss1.0000
18:742916:A:ACdonor_gain1.0000
18:742916:AC:Adonor_gain1.0000
18:742916:ACC:Adonor_loss1.0000
18:742917:C:CCdonor_gain1.0000
18:742917:CC:Cdonor_gain1.0000
18:742917:CCT:Cdonor_gain1.0000
18:742917:CCTT:Cdonor_gain1.0000
18:743093:TGTTC:Tacceptor_gain1.0000
18:743094:GTTC:Gacceptor_gain1.0000
18:743095:TTC:Tacceptor_gain1.0000
18:743095:TTCCT:Tacceptor_loss1.0000

AlphaMissense

3527 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
18:724447:A:GY537H1.000
18:724499:A:CF519L1.000
18:724499:A:TF519L1.000
18:724500:A:GF519S1.000
18:724501:A:GF519L1.000
18:724501:A:TF519I1.000
18:724508:T:AR516S1.000
18:724508:T:GR516S1.000
18:724509:C:AR516I1.000
18:724509:C:GR516T1.000
18:724510:T:CR516G1.000
18:724531:A:GW509R1.000
18:724531:A:TW509R1.000
18:724584:A:GM491T1.000
18:724611:A:GL482S1.000
18:732840:A:CY473D1.000
18:732840:A:GY473H1.000
18:732840:A:TY473N1.000
18:732842:G:CP472R1.000
18:732842:G:TP472Q1.000
18:732843:G:AP472S1.000
18:732843:G:TP472T1.000
18:732851:C:AG469V1.000
18:732851:C:TG469D1.000
18:732852:C:GG469R1.000
18:732863:A:GL465P1.000
18:732867:C:TE464K1.000
18:732875:A:GL461P1.000
18:732881:C:AG459V1.000
18:732881:C:TG459E1.000

dbSNP variants (sampled 300 via entrez): RS1000033153 (18:780994 G>C), RS1000041115 (18:722911 T>A,C), RS1000060924 (18:806223 C>A,T), RS1000070719 (18:806439 A>C,G), RS1000113407 (18:727768 A>G), RS1000115534 (18:741729 G>C), RS1000120993 (18:728315 C>T), RS1000146467 (18:766246 C>G), RS1000157730 (18:794598 C>G,T), RS1000202568 (18:806598 G>A), RS1000240477 (18:814145 T>A,G), RS1000305583 (18:754616 C>A), RS1000313116 (18:814306 C>A,G), RS1000338429 (18:733026 G>A), RS1000339486 (18:730691 C>T)

Disease associations

OMIM: gene MIM:164880 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

StudyTraitp-value
GCST001918_3Pulmonary function in asthmatics4.000000e-06
GCST002279_44PR interval in Tripanosoma cruzi seropositivity3.000000e-07
GCST005024_83Pursuit maintenance gain6.000000e-06
GCST005978_3Diastolic blood pressure7.000000e-10
GCST005979_4Systolic blood pressure5.000000e-11
GCST006010_17Mean arterial pressure3.000000e-12
GCST006624_106Systolic blood pressure2.000000e-21
GCST007267_39Systolic blood pressure6.000000e-16
GCST007703_77Systolic blood pressure3.000000e-11
GCST007704_29Diastolic blood pressure1.000000e-08
GCST007706_39Mean arterial pressure4.000000e-11
GCST007707_40Hypertension7.000000e-07
GCST009888_1Thyroid autoantibody positivity (anti-thyroglobulin (TgAb) and/or anti-thyroid peroxidase (TPOAb) levels)2.000000e-08

EFO canonical traits (6, from GWAS)

EFO IDTrait name
EFO:0003892pulmonary function measurement
EFO:0004462PR interval
EFO:0008433pursuit maintenance gain measurement
EFO:0006336diastolic blood pressure
EFO:0006335systolic blood pressure
EFO:0006340mean arterial pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2073 (SINGLE PROTEIN), CHEMBL2363074 (PROTEIN FAMILY), CHEMBL4523728 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

66 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 433,199 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL1171837PONATINIB48,955
CHEMBL1287853FEDRATINIB43,554
CHEMBL1289926AXITINIB415,732
CHEMBL1421DASATINIB ANHYDROUS455,003
CHEMBL180022NERATINIB49,404
CHEMBL1834657INFIGRATINIB PHOSPHATE4285
CHEMBL1852688INFIGRATINIB42,209
CHEMBL1873475IBRUTINIB47,994
CHEMBL2028663DABRAFENIB412,430
CHEMBL24828VANDETANIB442,230
CHEMBL255863NILOTINIB438,627
CHEMBL288441BOSUTINIB412,255
CHEMBL3301622GILTERITINIB42,395
CHEMBL3545311BRIGATINIB45,634
CHEMBL477772PAZOPANIB415,540
CHEMBL502835NINTEDANIB48,545
CHEMBL535SUNITINIB479,020
CHEMBL5416410DASATINIB4655
CHEMBL553ERLOTINIB4108,300
CHEMBL576982QUIZARTINIB44,432
CHEMBL601719CRIZOTINIB4
CHEMBL608533MIDOSTAURIN4
CHEMBL1908391MASITINIB3
CHEMBL217092SARACATINIB3
CHEMBL31965CANERTINIB3
CHEMBL3544983TESEVATINIB3
CHEMBL491473CEDIRANIB3
CHEMBL50QUERCETIN3
CHEMBL522892DOVITINIB3
CHEMBL572881MOTESANIB3

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 (9 total), top 9:

LigandActionAffinityParameter
eCF506Inhibition9.3pIC50
rebastinibInhibition8.82pIC50
saracatinibInhibition8.4pIC50
ibrutinibInhibition8.39pIC50
nemtabrutinibInhibition8.38pIC50
nefextinibInhibition8.24pIC50
SU6656Inhibition7.7pIC50
xiliertinibInhibition6.48pIC50
spebrutinibInhibition6.14pIC50

Binding affinities (BindingDB)

78 measured of 99 human assays (99 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValuePatent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]ureaKD0.37 nM
IBRUTINIBIC500.8 nMUS-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-enamideIC501.1 nMUS-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
StaurosporineKD1.7 nM
N-[3-(diethylaminomethoxy)phenyl]-7-(2,6-dimethylphenyl)-5-methyl-1,2,4-benzotriazin-3-amineIC502.6 nMUS-8481536: Benzotriazine inhibitors of kinases
5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-oneKD2.8 nM
3-[[2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridin-7-yl]amino]phenolIC505.1 nMUS-9062066: Anti-inflammatory compound having inhibitory activity against multiple tyrosine kinases and pharmaceutical composition containing same
3-[[7-(2-chloro-5-hydroxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]-N-[2-(dimethylamino)ethyl]benzamideIC505.3 nMUS-8481536: Benzotriazine inhibitors of kinases
N-[2-[[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[2-[4-(4-methylpiperazin-1-yl)anilino]-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-(4-acetylphenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-(6-methoxy-3-pyridinyl)-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[2-[4-(4-methylpiperazin-1-yl)anilino]-5-thiophen-2-ylpyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[2-[4-(4-methylpiperazin-1-yl)anilino]-5-[(4-phenoxyphenyl)methoxy]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-(2-chloro-6-methylphenyl)-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-4-[2-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-(2-chloro-6-methylphenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-4-[2-(propanoylamino)anilino]pyrimidine-5-carboxamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-(furan-3-yl)-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-(2-chloro-6-methylphenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-4-[2-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-[(4-methylphenyl)methoxy]-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-cyclopropyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-bromo-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-iodo-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[2-[4-(4-methylpiperazin-1-yl)anilino]thieno[3,2-d]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-(2,6-dichlorophenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-4-[2-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-(2,6-dimethylphenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-4-[2-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]-6-methylphenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]-3-fluorophenyl]prop-2-enamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-(2-chloro-6-methylphenyl)-4-[5-fluoro-2-(prop-2-enoylamino)anilino]-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidine-5-carboxamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-(2-chloro-6-methylphenyl)-4-[2-fluoro-6-(prop-2-enoylamino)anilino]-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidine-5-carboxamideIC505.5 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
4-chloro-3-[6-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenolIC505.7 nMUS-8481536: Benzotriazine inhibitors of kinases
7-(2,6-dimethylphenyl)-5-methyl-N-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amineIC506.4 nMUS-8481536: Benzotriazine inhibitors of kinases
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamideIC5010 nMUS-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
BIIB-057IC5010.5 nM
tert-butyl 4-amino-3-[2-[2-methyl-5-[[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]phenyl]ethynyl]pyrazolo[3,4-d]pyrimidine-1-carboxylateIC5011 nMUS-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenolIC5015.9 nMUS-8481536: Benzotriazine inhibitors of kinases
N-[3-[2-[4-amino-1-(1-methylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-3-(trifluoromethyl)benzamideIC5018 nMUS-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
7-(2,6-dimethylphenyl)-5-methyl-N-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-1,2,4-benzotriazin-3-amineIC5021 nMUS-8481536: Benzotriazine inhibitors of kinases
3-[2-[4-amino-1-(1-prop-2-enoylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamideIC5022 nMUS-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
BMS-354825KD27 nM
4-[[7-(2-chloro-5-hydroxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamideIC5030.8 nMUS-8481536: Benzotriazine inhibitors of kinases
7-(2,6-dichlorophenyl)-5-methyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amineIC5040 nMUS-8481536: Benzotriazine inhibitors of kinases
N-[4-(2-cyclopentylethoxy)phenyl]-7-(2,6-dimethylphenyl)-5-methyl-1,2,4-benzotriazin-3-amineIC5049 nMUS-8481536: Benzotriazine inhibitors of kinases
N-(2-chloro-6-methylphenyl)-2-[3-(4-methylpiperazin-1-yl)anilino]-4-[2-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamideIC5055 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[2-[4-(4-methylpiperazin-1-yl)anilino]furo[3,2-d]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC5055 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[6-amino-5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamideIC5055 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
N-[2-[[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]-4-methylphenyl]prop-2-enamideIC5055 nMUS-12365664: Small molecule inhibitors of SRC tyrosine kinase
7-(2-chlorophenyl)-5-methyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amineIC5058 nMUS-8481536: Benzotriazine inhibitors of kinases

ChEMBL bioactivities

314 potent at pChembl≥5 of 333 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
9.52IC500.3nMCHEMBL400402
9.52Kd0.3nMDASATINIB
9.41IC500.39nMCHEMBL5280844
9.40IC500.4nMBOSUTINIB
9.30IC500.5nMDASATINIB
9.30IC500.5nMCHEMBL400402
9.30IC500.5nMCHEMBL364623
9.15IC500.7nMSARACATINIB
9.15IC500.7nMCHEMBL3651257
9.10IC500.8nMCHEMBL3426225
9.10IC500.8nMCHEMBL3647967
9.05IC500.89nMPONATINIB
9.00Kd1nMCHEMBL400402
9.00IC501nMCHEMBL436137
9.00IC501nMAT-9283
9.00IC501nMCHEMBL4798527
9.00Kd1nMCHEMBL249097
8.92IC501.2nMCHEMBL3651296
8.92IC501.2nMCHEMBL436137
8.91IC501.24nMCHEMBL3651228
8.89IC501.28nMCHEMBL249821
8.89IC501.3nMCHEMBL249821
8.89IC501.3nMCHEMBL5268244
8.85IC501.4nMDOVITINIB
8.82IC501.5nMREBASTINIB
8.77IC501.7nMSTAUROSPORINE
8.70IC502nMCHEMBL364623
8.70IC502nMCHEMBL3426233
8.68IC502.1nMCHEMBL2336005
8.64IC502.3nMCHEMBL5280361
8.64Kd2.3nMCHEMBL386051
8.63IC502.35nMSTAUROSPORINE
8.62IC502.39nMSTAUROSPORINE
8.60IC502.5nMREBASTINIB
8.59IC502.6nMCHEMBL3651297
8.59IC502.6nMCHEMBL218102
8.59IC502.56nMSTAUROSPORINE
8.52IC503nMCHEMBL457614
8.52IC503nMCHEMBL217090
8.51IC503.1nMCHEMBL231218
8.43IC503.7nMCHEMBL218549
8.43Kd3.715nMDASATINIB ANHYDROUS
8.40IC504nMCHEMBL3923175
8.40IC504nMSARACATINIB
8.40Kd4nMDASATINIB
8.40Kd4nMDASATINIB ANHYDROUS
8.40Kd4nMBOSUTINIB
8.39IC504.1nMCHEMBL250625
8.39IC504.1nMIBRUTINIB
8.36IC504.4nMSTAUROSPORINE

PubChem BioAssay actives

249 with measured affinity, of 2303 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.

CompoundAssayTypeValueUnit
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate435328: Binding constant for YES kinase domainkd0.0003uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol325210: Inhibition of YESic500.0003uM
(2-chloro-4-phenoxyphenyl)-[4-[[(6S)-6-(hydroxymethyl)oxan-3-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone1939138: Inhibition of YES (unknown origin)ic500.0004uM
Bosutinib507428: Inhibition of YES1ic500.0004uM
tert-butyl N-[4-[4-amino-1-[2-[4-(dimethylamino)piperidin-1-yl]ethyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl]carbamate1310132: Inhibition of human YES using poly[Glu,Tyr]4:1 as substrate in presence of [gamma-33P] ATPic500.0005uM
N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(oxan-4-yloxy)quinazolin-4-amine761477: Inhibition of Yes1 (unknown origin) by [gamma-33P]-ATP radiolabeled enzyme activity assayic500.0007uM
3-[2-(4-amino-1-ethylpyrazolo[3,4-d]pyrimidin-3-yl)ethynyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide1206221: Inhibition of human Yesic500.0008uM
Ponatinib1716395: Binding affinity to human YES using poly[Glu:Tyr] (4:1) as substrate by radiometric hotspot kinase assayic500.0009uM
7-(2,6-dimethylphenyl)-5-methyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amine276183: Inhibition of Yesic500.0010uM
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide1734743: Inhibition of human full length recombinant YES using poly(Glu,Tyr)4:1 as substrate incubated for 40 mins in presence of [gamma33P-ATP] by radiometric scintillation counting analysisic500.0010uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea412621: Inhibition of Yesic500.0010uM
3-[[4-(5-hydroxy-2-methylanilino)pyrimidin-2-yl]amino]benzamide389065: Binding affinity to human YESkd0.0010uM
4-[[7-(2-chloro-5-hydroxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamide325210: Inhibition of YESic500.0013uM
[(2S,3R,4R,5R)-5-[4-amino-3-(4-methylphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-3-methyl-4-prop-2-ynoxyoxolan-2-yl]methyl 4-fluorosulfonylbenzoate1940020: Inhibition of YES (unknown origin)ic500.0013uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one761477: Inhibition of Yes1 (unknown origin) by [gamma-33P]-ATP radiolabeled enzyme activity assayic500.0014uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide761477: Inhibition of Yes1 (unknown origin) by [gamma-33P]-ATP radiolabeled enzyme activity assayic500.0015uM
(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-one2198460: Inhibition of human YES using poly[Glu:Tyr] (4:1) as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assayic500.0017uM
N-(2-chloro-6-methylphenyl)-2-[(2,6-dimethylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide271968: Inhibition of Yesic500.0020uM
[(2S,3R,4R,5R)-5-[4-amino-3-(4-methylphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-3-methyl-4-prop-2-ynoxyoxolan-2-yl]methyl ethenesulfonate1940020: Inhibition of YES (unknown origin)ic500.0023uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one625018: Binding constant for YES kinase domainkd0.0023uM
N-(5-chloro-1,3-benzodioxol-4-yl)-5-(oxan-4-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine272224: Inhibition of recombinant C-YES by ELISAic500.0030uM
5-chloro-2-N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-4-N-(3-propan-2-yloxy-1H-pyrazol-5-yl)pyrimidine-2,4-diamine761477: Inhibition of Yes1 (unknown origin) by [gamma-33P]-ATP radiolabeled enzyme activity assayic500.0030uM
Dasatinib2149796: Binding affinity to human YES1 incubated for 45 mins by Kinobead based pull down assaykd0.0037uM
2-[[N-[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]-5-(hydroxymethyl)-2-methylanilino]methyl]benzonitrile1326072: Inhibition of N-terminal 6His-tagged full length recombinant human YES expressed in baculovirus expression systemic500.0040uM
4-chloro-3-[5-methyl-3-(4-piperidin-4-ylsulfonylanilino)-1,2,4-benzotriazin-7-yl]phenol325210: Inhibition of YESic500.0041uM
Ibrutinib2188603: Inhibition of recombinant YES1 (unknown origin) preincubated for 1 hr in presence of ATP by Z-Lyte assayic500.0041uM
4-chloro-3-[5-methyl-3-[4-(3-pyrrolidin-1-ylpropyl)anilino]-1,2,4-benzotriazin-7-yl]phenol325210: Inhibition of YESic500.0048uM
6-amino-7-(4-phenoxyphenyl)-9-[(3S)-1-prop-2-enoylpiperidin-3-yl]purin-8-one1425212: 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.kd0.0050uM
[4-[[7-(2-chloro-5-hydroxyphenyl)-5-methyl-1,2,4-benzotriazin-3-yl]amino]phenyl]-piperazin-1-ylmethanone325210: Inhibition of YESic500.0052uM
7-(2,6-dichlorophenyl)-5-methyl-N-[4-[2-(1-oxidopyrrolidin-1-ium-1-yl)ethoxy]phenyl]-1,2,4-benzotriazin-3-amine330573: Inhibition of Yes by luminescence based kinase assayki0.0060uM
4-methyl-3-[[3-[2-(methylamino)pyrimidin-4-yl]-2-pyridinyl]oxy]-N-[3-(trifluoromethyl)phenyl]benzamide761478: Inhibition of Yes1 (unknown origin) assessed as kinase-dependent enzymatic production of ADP from ATP using coupled luminescence-based reaction by ADP-Glo kinase assayic500.0087uM
(3Z)-3-[[3-[3-(dimethylamino)propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl]methylidene]-N-methyl-2-oxo-1H-indole-5-sulfonamide220258: Inhibitory activity against Yes tyrosine kinaseic500.0100uM
3-[2-[(Z)-[5-(methylsulfamoyl)-2-oxo-1H-indol-3-ylidene]methyl]-4,5,6,7-tetrahydro-1H-indol-3-yl]propanamide220258: Inhibitory activity against Yes tyrosine kinaseic500.0100uM
2-[4-[3-[2-[(Z)-[5-(methylsulfamoyl)-2-oxo-1H-indol-3-ylidene]methyl]-4,5,6,7-tetrahydro-1H-indol-3-yl]propyl]piperazin-1-yl]acetic acid220258: Inhibitory activity against Yes tyrosine kinaseic500.0100uM
7-(2,6-dichlorophenyl)-5-methyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,2,4-benzotriazin-3-amine325210: Inhibition of YESic500.0100uM
2-[4-[3-[2-[(Z)-(5-ethylsulfonyl-2-oxo-1H-indol-3-ylidene)methyl]-4,5,6,7-tetrahydro-1H-indol-3-yl]propyl]piperazin-1-yl]acetic acid220258: Inhibitory activity against Yes tyrosine kinaseic500.0100uM
(3Z)-3-[[3-[3-(4-hydroxypiperidin-1-yl)propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl]methylidene]-N-methyl-2-oxo-1H-indole-5-sulfonamide220258: Inhibitory activity against Yes tyrosine kinaseic500.0100uM
(3Z)-N-methyl-3-[[3-[3-(4-methylpiperazin-1-yl)propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl]methylidene]-2-oxo-1H-indole-5-sulfonamide220258: Inhibitory activity against Yes tyrosine kinaseic500.0100uM
(3Z)-3-[[3-[3-[4-(2-hydroxyethyl)piperazin-1-yl]propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl]methylidene]-N-methyl-2-oxo-1H-indole-5-sulfonamide220258: Inhibitory activity against Yes tyrosine kinaseic500.0100uM
1-[2-[4-[(dimethylamino)methyl]piperidin-1-yl]ethyl]-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[3,4-d]pyrimidin-4-amine1310132: Inhibition of human YES using poly[Glu,Tyr]4:1 as substrate in presence of [gamma-33P] ATPic500.0120uM
4-[8-amino-3-[(6R,8aS)-3-oxo-2,5,6,7,8,8a-hexahydro-1H-indolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]benzamide1721761: Inhibition of YES1 (unknown origin)ic500.0120uM
6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine761477: Inhibition of Yes1 (unknown origin) by [gamma-33P]-ATP radiolabeled enzyme activity assayic500.0131uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone625018: Binding constant for YES kinase domainkd0.0180uM
Brigatinib2182804: Inhibition of human YES1 using poly (Glu, Tyr)4:1 as substrate in presence of [gamma33P]-ATP by HotSpot assayic500.0190uM
3-chloro-4-[3-(5-chloro-1,3-dioxopyrido[1,2-c]pyrimidin-2-yl)-2-methylphenyl]-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide1678397: Inhibition of YES1 (unknown origin)ic500.0190uM
ethyl 2-[4-[3-[2-[(Z)-[5-(methylsulfamoyl)-2-oxo-1H-indol-3-ylidene]methyl]-4,5,6,7-tetrahydro-1H-indol-3-yl]propyl]piperazin-1-yl]acetate220258: Inhibitory activity against Yes tyrosine kinaseic500.0200uM
(3Z)-5-ethylsulfonyl-3-[[3-[3-(4-hydroxypiperidin-1-yl)propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl]methylidene]-1H-indol-2-one220258: Inhibitory activity against Yes tyrosine kinaseic500.0200uM
(3Z)-N,N-dimethyl-2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylidene)-1H-indole-5-sulfonamide325713: Inhibition of Yes kinaseic500.0200uM
(3Z)-3-[[3-[3-(dimethylamino)propyl]-4,5,6,7-tetrahydro-1H-indol-2-yl]methylidene]-5-ethylsulfonyl-1H-indol-2-one220258: Inhibitory activity against Yes tyrosine kinaseic500.0200uM
4-[8-amino-3-[(3R,6S)-1-(cyclopropanecarbonyl)-6-methylpiperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl]-3-fluoro-N-[4-(trifluoromethyl)-2-pyridinyl]benzamide1711668: Inhibition of human YES1ic500.0210uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
bisphenol Adecreases expression, increases expression2
sodium arseniteincreases abundance, increases expression2
Arsenicaffects methylation, increases abundance, increases expression2
Benzo(a)pyrenedecreases expression, affects methylation2
Tobacco Smoke Pollutionaffects expression, increases expression2
aristolochic acid Idecreases expression1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamidedecreases expression1
bisphenol Fincreases expression1
2,4,6-tribromophenolincreases expression1
triphenyl phosphateaffects expression1
alpha-pineneaffects cotreatment, increases oxidation, increases abundance1
pyrogallol 1,3-dimethyl etherincreases expression, affects cotreatment, affects localization1
decabromobiphenyl etherincreases expression1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acidaffects methylation, increases abundance1
cobaltous chlorideincreases phosphorylation, increases expression, increases secretion, decreases reaction1
2-bromopalmitatedecreases reaction, increases abundance, increases palmitoylation1
benzo(e)pyrenedecreases methylation1
4-hydroxy-2-nonenaldecreases expression1
1-hydroxypyreneaffects cotreatment, decreases methylation1
HC toxinincreases expression1
methacrylaldehydeaffects cotreatment, increases oxidation, increases abundance1
dibenzo(a,l)pyrenedecreases expression1
chromium hexavalent iondecreases activity1
perfluorooctane sulfonic aciddecreases expression1
CGP 52608affects binding, increases reaction1
K 7174increases expression1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideincreases expression1
bisphenol Bincreases expression1
6-O-carboxypropyl-alpha-tocotrienoldecreases reaction, increases phosphorylation1
bisphenol Sincreases expression1

ChEMBL screening assays

514 unique, capped per target: 509 binding, 3 admet, 2 functional

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1009922BindingInhibition of YesFragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. — J Med Chem
CHEMBL2354304FunctionalPubChem BioAssay. qHTS for small molecule inhibitors of Yes1 kinase: Confirmatory screen on the cherrypicks. (Class of assay: confirmatory)PubChem BioAssay data set
CHEMBL4313108ADMETInhibition of recombinant full-length human Yes at 100 nM using poly(Glu, Tyr) 4:1 as substrate measured after 40 mins in presence of [gamma33P]ATP by scintillation counting methodDiscovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design. — J Med Chem

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

CellosaurusNameCategorySex
CVCL_B2LKAbcam HeLa YES1 KOCancer cell lineFemale
CVCL_C8INK562/fes clone WS-1Cancer cell lineFemale
CVCL_C8IPK562/fes clone WS-5Cancer cell lineFemale
CVCL_C8IQK562/fes clone WS-6Cancer cell lineFemale
CVCL_TY45HAP1 YES1 (-) 1Cancer cell lineMale
CVCL_TY46HAP1 YES1 (-) 2Cancer cell lineMale

Clinical trials (associated diseases)

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