STAT3

Summary

STAT3 (signal transducer and activator of transcription 3, HGNC:11364) is a protein-coding gene on chromosome 17q21.2, encoding Signal transducer and activator of transcription 3 (P40763). Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors.

The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome.

Source: NCBI Gene 6774 — RefSeq curated summary.

At a glance

• Gene–disease (curated): STAT3-related early-onset multisystem autoimmune disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 34
• Clinical variants (ClinVar): 908 total — 42 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 177
• Druggable target: yes — 18 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• Transcription factor: yes — 454 downstream targets (CollecTRI)
• MANE Select transcript: NM_139276

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11364
Approved symbol	STAT3
Name	signal transducer and activator of transcription 3
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	APRF
Ensembl gene	ENSG00000168610
Ensembl biotype	protein_coding
OMIM	102582
Entrez	6774

Gene structure

Transcript identifiers

Ensembl transcripts: 94 — 72 protein_coding, 12 retained_intron, 5 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay

ENST00000264657, ENST00000389272, ENST00000404395, ENST00000462269, ENST00000462286, ENST00000471989, ENST00000478276, ENST00000491272, ENST00000498330, ENST00000585360, ENST00000585517, ENST00000588969, ENST00000590776, ENST00000676636, ENST00000677002, ENST00000677030, ENST00000677152, ENST00000677270, ENST00000677271, ENST00000677308, ENST00000677346, ENST00000677421, ENST00000677442, ENST00000677479, ENST00000677500, ENST00000677603, ENST00000677723, ENST00000677763, ENST00000677820, ENST00000678043, ENST00000678044, ENST00000678048, ENST00000678108, ENST00000678445, ENST00000678529, ENST00000678535, ENST00000678572, ENST00000678659, ENST00000678674, ENST00000678764, ENST00000678792, ENST00000678827, ENST00000678905, ENST00000678906, ENST00000678913, ENST00000678960, ENST00000679014, ENST00000679166, ENST00000679185, ENST00000679231, ENST00000715205, ENST00000858552, ENST00000858553, ENST00000858554, ENST00000858555, ENST00000858556, ENST00000858557, ENST00000858558, ENST00000858559, ENST00000858560, ENST00000858561, ENST00000858562, ENST00000922763, ENST00000922764, ENST00000922765, ENST00000922766, ENST00000922767, ENST00000922768, ENST00000922769, ENST00000922770, ENST00000943782, ENST00000943783, ENST00000943784, ENST00000943785, ENST00000943786, ENST00000943787, ENST00000943788, ENST00000943789, ENST00000943790, ENST00000943791, ENST00000943792, ENST00000943793, ENST00000943794, ENST00000943795, ENST00000943796, ENST00000943797, ENST00000943798, ENST00000943799, ENST00000943800, ENST00000943801, ENST00000943802, ENST00000943803, ENST00000943804, ENST00000943805

RefSeq mRNA: 21 — MANE Select: NM_139276 NM_001369512, NM_001369513, NM_001369514, NM_001369516, NM_001369517, NM_001369518, NM_001369519, NM_001369520, NM_001384984, NM_001384985, NM_001384986, NM_001384987, NM_001384988, NM_001384989, NM_001384990, NM_001384991, NM_001384992, NM_001384993, NM_003150, NM_139276, NM_213662

CCDS: CCDS32656, CCDS32657, CCDS59288, CCDS92309, CCDS92310, CCDS92311, CCDS92312, CCDS92313, CCDS92314, CCDS92315, CCDS92316

Canonical transcript exons

ENST00000264657 — 24 exons

Exon	Start	End
ENSE00000725380	42339314	42339409
ENSE00000950719	42329410	42329457
ENSE00000950720	42326116	42326199
ENSE00000950725	42323004	42323143
ENSE00001179541	42322282	42322494
ENSE00001228108	42329554	42329647
ENSE00001228116	42329747	42329776
ENSE00001228122	42331472	42331531
ENSE00001228128	42333673	42333765
ENSE00001228134	42333891	42334049
ENSE00001228140	42337435	42337586
ENSE00001302308	42348389	42348539
ENSE00001505324	42337763	42337857
ENSE00001505325	42338731	42338812
ENSE00001835049	42313324	42315800
ENSE00002832033	42317182	42317224
ENSE00002972150	42388279	42388442
ENSE00003463278	42323260	42323354
ENSE00003466416	42316789	42316901
ENSE00003503687	42324963	42325061
ENSE00003504262	42323573	42323625
ENSE00003534325	42324711	42324846
ENSE00003551986	42346569	42346713
ENSE00003631188	42345559	42345657

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.1404 / max 981.7375, expressed in 1826 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166145	50.5192	1825
166146	8.5063	1781
166139	0.2553	64
166134	0.2037	52
166147	0.1992	73
166133	0.1740	53
166138	0.1321	49
166132	0.0848	36
166141	0.0535	19
166140	0.0123	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.31	gold quality
pericardium	UBERON:0002407	99.12	gold quality
lower lobe of lung	UBERON:0008949	99.05	gold quality
mammary duct	UBERON:0001765	98.47	gold quality
nipple	UBERON:0002030	98.41	gold quality
heart right ventricle	UBERON:0002080	98.29	gold quality
upper lobe of lung	UBERON:0008948	98.23	gold quality
upper lobe of left lung	UBERON:0008952	98.22	gold quality
islet of Langerhans	UBERON:0000006	98.14	gold quality
vena cava	UBERON:0004087	98.13	gold quality
colonic epithelium	UBERON:0000397	98.12	gold quality
trachea	UBERON:0003126	98.00	gold quality
epithelium of mammary gland	UBERON:0003244	98.00	gold quality
cartilage tissue	UBERON:0002418	97.93	gold quality
dorsal root ganglion	UBERON:0000044	97.88	gold quality
penis	UBERON:0000989	97.87	gold quality
left uterine tube	UBERON:0001303	97.86	gold quality
trigeminal ganglion	UBERON:0001675	97.83	gold quality
blood	UBERON:0000178	97.82	gold quality
pharyngeal mucosa	UBERON:0000355	97.80	gold quality
superior surface of tongue	UBERON:0007371	97.74	gold quality
urethra	UBERON:0000057	97.71	gold quality
gall bladder	UBERON:0002110	97.70	gold quality
saphenous vein	UBERON:0007318	97.69	gold quality
synovial joint	UBERON:0002217	97.67	gold quality
right lung	UBERON:0002167	97.64	gold quality
peritoneum	UBERON:0002358	97.63	gold quality
decidua	UBERON:0002450	97.62	gold quality
omental fat pad	UBERON:0010414	97.62	gold quality
left ventricle myocardium	UBERON:0006566	97.59	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	43.43
E-CURD-88	yes	42.24
E-HCAD-25	yes	4.22
E-GEOD-137537	no	1696.17
E-MTAB-4850	no	1470.72
E-CURD-112	no	2.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

454 targets.

Target	Regulation
A2M	Unknown
AATF
ABCA1	Unknown
ABCA3	Activation
ABCB1	Unknown
ACACA	Activation
ACOX1	Repression
ACTG2	Activation
ADAM2
ADAMTS13	Repression
ADAMTS4	Unknown
ADIPOQ
ADM	Activation
AGRP	Unknown
AGT	Unknown
AHR	Activation
AKAP12	Activation
AKT1	Unknown
ANXA1	Unknown
AP1	Activation
APCS	Unknown
APEX1	Activation
APLN	Activation
APOA4	Activation
APP	Unknown
AR	Unknown
ARG1
ARID5A	Activation
BACE1
BAD	Activation

JASPAR motifs

Motif	Name	Family
MA0144.2	STAT3	STAT factors
MA0144.3	STAT3	STAT factors

JASPAR matrix evidence (PMIDs): PMID:18555785

Upstream regulators (CollecTRI, top): AP1, ATF4, BANP, BATF, BCL6, BRCA1, CEBPA, CEBPB, CREB1, CTNNB1, ETV6, HDAC1, HIC1, HIF1A, HMGA1, JAK1, JUN, KAT5, MYC, PIAS3, PLK1, POLR2H, PPARG, RELA, SIN3A, SPI1, STAT1, STAT3, STAT5A, TCF7L2, TP53, TRPS1, ZNF382

miRNA regulators (miRDB)

158 targeting STAT3, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma (PMID:11751994)
• Modulation of signal transducer and activator of transcription 3 activities by p53 tumor suppressor in breast cancer cells. (PMID:11809683)
• Cytokine signaling: STATS in plasma membrane rafts (PMID:11815625)
• actdivated by fiboblst growth factor 3 and adapter protein SH-B (PMID:11827956)
• Stat1 and Stat3 may support cell growth in part via c-myc gene activation in primary erythroleukemia cells. (PMID:11843291)
• inhibits gamma-globin gene expression in erythroid cells. (PMID:11856732)
• Breast Carcinoma cell growth could be inhibited by dominant-negative versions of STAT3. (PMID:11859072)
• STAT3 isoforms are differentially expressed and phosphorylated during progression of granulocytic differentiation. (PMID:11861277)
• The C-terminal domain of Stat3 negatively regulates its receptor binding activity only in the absence of the first alpha-helix of the coiled-coil domain, which leads to a hypothesis of intramolecular interaction. (PMID:11872739)
• The transforming capacity of constitutively activated STAT3 and STAT5 mutants strongly supports their fundamental role in the process of malignant transformation in hematopoietic cells (PMID:11882364)
• IL-6-inducible expression of the hAGT promoter is mediated by physical association of the COOH terminus of STAT3 with p300/CBP, the recruitment of which targets histone acetylation and results in chromatin remodeling. (PMID:11923478)
• STAT5b-RARalpha and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway. (PMID:11929748)
• Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet-activating factor, JAK-2, and Src in human umbilical vein endothelial cells (PMID:11940567)
• Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells. (PMID:11959895)
• Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis (PMID:11960372)
• Stat3 activity is significantly increased in both prostate cancer and adjacent normal prostate tissue; activation may be an early event in prostatic epithelial carcinogenesis (PMID:11987152)
• Stat3 and GRP58 were observed to be coassociated with cytoplasmic membranes (PMID:12060494)
• activated in human ovaarian carcinoma; co-expressed with oncostatin M and its receptor (PMID:12061840)
• Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. (PMID:12067972)
• activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c (PMID:12105218)
• STAT3 is activated by HGF/HGFR and has a role in fetal organogenesis and placental tissue (PMID:12168776)
• constitutive STAT3 activation contributes to tumor growth in SCCHN, independent of the EGFR autocrine axis. (PMID:12193474)
• Data show that IL-6/raft/STAT3 signaling is a chaperoned pathway that involves caveolin-1 and HSP90 as accessory proteins and suggest a mechanism for the preservation of this signaling during fever. (PMID:12235142)
• The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through its dephosphorylation. (PMID:12359225)
• PKC delta associates with IL6ST via Stat3 and enhances Stat3-gp130 interaction (PMID:12361954)
• Platelet signaling pathways activated by thrombopoietin may affect mitochondrial transcription via activation of mitochondrial STAT3 (PMID:12389630)
• findings suggest that activated STAT3 signaling directly contributes to malignant progression of primary effusion lymphoma by preventing apoptosis, acting through the prosurvival protein survivin (PMID:12393476)
• selectively activated in immature dendritic cells by expression of HIV nef (PMID:12396456)
• Schwannomin and HRS inhibit Stat3 activation in schwannoma cells. (PMID:12444102)
• ablation of Stat3 function converts EGF from a growth/survival factor for RA synoviocytes to a death factor (PMID:12444174)
• Inhibition suppresses proliferation and induces apoptosis in glioblastoma multiforme cells (PMID:12466961)
• Dysregulated STAT3 activity by PML/RAR alpha may participate in the pathogenesis of APL. (PMID:12506013)
• Kaposi sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through inhibition of this protein. (PMID:12531804)
• Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer (PMID:12545153)
• expression and DNA-binding activity of this protein in alcoholic cirrhosis compared to normal liver and primary biliary cirrhosis in humans (PMID:12547716)
• identification of tip60 as a co-repressor for STAT3 (PMID:12551922)
• inhibition by differentiation-inducing factor-1 is involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway (PMID:12555068)
• This protein is activated by leptin which activates the FAAH promoter in T cells. (PMID:12556536)
• Ataxia telangiectasia mutated proteins, MAPKs, and RSK2 are involved in the phosphorylation of this protein. (PMID:12562765)
• THE presence of this protein and its phosphorylated derivative in node-negative breast cancer shows nuclear localization is associated with a better prognosis. (PMID:12576423)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	stat3	ENSDARG00000022712
mus_musculus	Stat3	ENSMUSG00000004040
rattus_norvegicus	Stat3	ENSRNOG00000019742
caenorhabditis_elegans		WBGENE00010251
caenorhabditis_elegans		WBGENE00013111

Paralogs (6): STAT1 (ENSG00000115415), STAT5A (ENSG00000126561), STAT4 (ENSG00000138378), STAT6 (ENSG00000166888), STAT2 (ENSG00000170581), STAT5B (ENSG00000173757)

Protein

Protein identifiers

Signal transducer and activator of transcription 3 — P40763 (reviewed: P40763)

Alternative names: Acute-phase response factor

All UniProt accessions (16): P40763, A0A7I2V2G1, A0A7I2V2T1, A0A7I2V395, A0A7I2V3V0, A0A7I2V444, A0A7I2V4C8, A0A7I2V4F6, A0A7I2V4R2, A0A7I2V4R3, A0A7I2V552, A0A7I2V5N9, A0A7I2YQD2, A0A7I2YQI1, A0A7I2YQR5, G8JLH9

UniProt curated annotations — full annotation on UniProt →

Function. Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors. Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Upon activation of IL6ST/gp130 signaling by interleukin-6 (IL6), binds to the IL6-responsive elements identified in the promoters of various acute-phase protein genes. Activated by IL31 through IL31RA. Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): acetylation promotes its transcription activity and cell differentiation while deacetylation and oxidation of lysine residues by LOXL3 inhibits differentiation. Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1. Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation. May play an apoptotic role by transctivating BIRC5 expression under LEP activation. Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity. Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion. Following JAK/STAT signaling activation and as part of a complex with NFATC3 and NFATC4, binds to the alpha-beta E4 promoter region of CRYAB and activates transcription in cardiomyocytes.

Subunit / interactions. Forms a homodimer or a heterodimer with a related family member (at least STAT1). Component of a promoter-binding complex composed of STAT3, NFATC3 and NFATC4; complex formation is enhanced by calcineurin. Interacts with IL31RA, NCOA1, PELP1, SIPAR, SOCS7, STATIP1 and TMF1. Interacts with IL23R in presence of IL23. Interacts (via SH2 domain) with NLK. Interacts with ARL2BP; the interaction is enhanced by LIF and JAK1 expression. Interacts with KPNA4 and KPNA5; KPNA4 may be the primary mediator of nuclear import. Interacts with CAV2; the interaction is increased on insulin-induced tyrosine phosphorylation of CAV2 and leads to STAT3 activation. Interacts with ARL2BP; interaction is enhanced with ARL2. Interacts with NEK6. Binds to CDK9 when activated and nuclear. Interacts with BMX. Interacts with ZIPK/DAPK3. Interacts with PIAS3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3. In prostate cancer cells, interacts with PRKCE and promotes DNA binding activity of STAT3. Interacts with STMN3, antagonizing its microtubule-destabilizing activity. Interacts with the ‘Lys-129’ acetylated form of BIRC5/survivin. Interacts with FER. Interacts (via SH2 domain) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with INPP5F; the interaction is independent of STAT3 Tyr-705 phosphorylation status. Interacts with FGFR4. Interacts with OCIAD1. Interacts with OCIAD2. Interacts (unphosphorylated or phosphorylated at Ser-727) with PHB1. Interacts and may form heterodimers with NHLH1. Found in a complex with SLC39A6, SLC39A10 and with the ‘Ser-727’ phosphorylated form of STAT3 throughout mitosis. Interacts (when phosphorylated at Tyr-705) with CD274/PD-L1; promoting nuclear translocation of CD274/PD-L1. Interacts (when acetylated) with EP300 (via bromo domain); interaction takes place following STAT3 acetylation by EP300 and promotes enhanceosome assembly. Interacts (when acetylated) with BRD2 (via bromo domain); interaction promotes STAT3 recruitment to chromatin and T-helper Th17 cell differentiation. Interacts with FAM220A/SIPAR; the interaction occurs in both the nucleus and the cytoplasm, is enhanced by IL6 and promotes STAT3 dephosphorylation. Interacts in both unphosphorylated and phosphorylated forms with FAM220A but interacts preferentially in the phosphorylated form in the nucleus. Interacts with PTPN2; the interaction is promoted by FAM220A and leads to STAT3 dephosphorylation which negatively regulates STAT3 transcriptional activator activity. (Microbial infection) Interacts with HCV core protein. (Microbial infection) Interacts with S.typhimurium SarA. (Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction leads to STAT3 nuclear accumulation and disruption of IL6-induced STAT3 phosphorylation.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in naive CD4(+) T cells as well as T-helper Th17, Th1 and Th2 cells.

Post-translational modifications. Tyrosine phosphorylated upon stimulation with EGF. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Activated through tyrosine phosphorylation by BMX. Tyrosine phosphorylated in response to IL6, IL11, LIF, CNTF, KITLG/SCF, CSF1, EGF, PDGF, IFN-alpha, LEP and OSM. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Phosphorylated on serine upon DNA damage, probably by ATM or ATR. Serine phosphorylation is important for the formation of stable DNA-binding STAT3 homodimers and maximal transcriptional activity. ARL2BP may participate in keeping the phosphorylated state of STAT3 within the nucleus. Upon LPS challenge, phosphorylated within the nucleus by IRAK1. Upon erythropoietin treatment, phosphorylated on Ser-727 by RPS6KA5. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates IL6/interleukin-6 signaling. Phosphorylation at Tyr-705 by PTK6, isoform M2 of PKM (PKM2) or FER leads to an increase of its transcriptional activity. Phosphorylation at Tyr-705 is increased in the presence of calcineurin. Phosphorylation at Tyr-640 by TYK2 negatively regulates transcriptional activity. Acetylated on lysine residues by EP300/p300, promoting its activation. Acetylation at Lys-49 and Lys-87 by EP300/p300 promotes its activation. Acetylation at Lys-87 by EP300/p300 promotes its association with BRD2 and recruitment to chromatin. Deacetylated at Lys-49 and Lys-87 by HDAC1. Acetylation at Lys-685 by EP300/p300 promotes its homodimerization and activation. Deacetylated at Lys-685 by HDAC3. Acetylated on lysine residues by CREBBP. Deacetylation by LOXL3 leads to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated. Some lysine residues are oxidized to allysine by LOXL3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated. (Microbial infection) Phosphorylated on Tyr-705 in the presence of S.typhimurium SarA. Methylated at Lys-140. Demethylation at Lys-140 by Jmjd1c facilitates its dephosphorylation by Ptpn6.

Disease relevance. Hyper-IgE syndrome 1, autosomal dominant, with recurrent infections (HIES1) [MIM:147060] A rare disorder of immunity and connective tissue characterized by immunodeficiency, chronic eosinophilia, distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures. The disease is caused by variants affecting the gene represented in this entry. Autoimmune disease, multisystem, infantile-onset, 1 (ADMIO1) [MIM:615952] A disorder characterized by early childhood onset of a spectrum of autoimmune manifestations affecting multiple organs, including insulin-dependent diabetes mellitus and autoimmune enteropathy or celiac disease. Other features include short stature, non-specific dermatitis, hypothyroidism, autoimmune arthritis, and delayed puberty. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Involved in the gp130-mediated signaling pathway.

Similarity. Belongs to the transcription factor STAT family.

Isoforms (3)

UniProt ID	Names	Canonical?
P40763-1	1	yes
P40763-2	Del-701
P40763-3	3

RefSeq proteins (21): NP_001356441, NP_001356442, NP_001356443, NP_001356445, NP_001356446, NP_001356447, NP_001356448, NP_001356449, NP_001371913, NP_001371914, NP_001371915, NP_001371916, NP_001371917, NP_001371918, NP_001371919, NP_001371920, NP_001371921, NP_001371922, NP_003141, NP_644805, NP_998827 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001217	STAT	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR012345	STAT_TF_DNA-bd_N	Homologous_superfamily
IPR013799	STAT_TF_prot_interaction	Domain
IPR013800	STAT_TF_alpha	Domain
IPR013801	STAT_TF_DNA-bd	Domain
IPR015988	STAT_TF_CC	Homologous_superfamily
IPR035855	STAT3_SH2	Domain
IPR036535	STAT_N_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR048988	STAT_linker	Domain

Pfam: PF00017, PF01017, PF02864, PF02865, PF21354

UniProt features (148 total): sequence variant 70, helix 19, modified residue 18, strand 16, mutagenesis site 7, sequence conflict 7, turn 4, splice variant 3, initiator methionine 1, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6NJS	X-RAY DIFFRACTION	2.7
6QHD	X-RAY DIFFRACTION	2.85
6TLC	X-RAY DIFFRACTION	2.9
5AX3	X-RAY DIFFRACTION	2.98
6NUQ	X-RAY DIFFRACTION	3.15
5U5S	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40763-F1	85.80	0.70

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (18): 615, 615, 631, 631, 640, 704, 685, 685, 705, 707, 714, 727, 2, 49, 87, 140, 601, 601

Mutagenesis-validated functional residues (7):

Position	Phenotype
705	inhibits leptin-mediated transactivation of ccnd1 promoter. abolished phosphorylation by isoform m2 of pkm (pkm2).
49	mimics acetylation; increased interaction with ep300; when associated with q-87.
49	decreased transcription activator activity and interaction with ep300; when associated with r-87.
87	mimics acetylation; increased interaction with ep300; when associated with q-49.
87	decreased transcription activator activity and interaction with ep300; when associated with r-49.
434–435	inhibits leptin-mediated transactivation of ccnd1 promoter. no effect on interaction with inpp5f.
685	decreased acetylation by ep300/p300, leading to impaired homodimerization and activation.

Function

Pathways and Gene Ontology

Reactome pathways

76 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-111453	BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members
R-HSA-1266695	Interleukin-7 signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1839117	Signaling by cytosolic FGFR1 fusion mutants
R-HSA-186763	Downstream signal transduction
R-HSA-198745	Signalling to STAT3
R-HSA-201556	Signaling by ALK
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2586552	Signaling by Leptin
R-HSA-2892247	POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8849474	PTK6 Activates STAT3
R-HSA-8854691	Interleukin-20 family signaling
R-HSA-8875791	MET activates STAT3
R-HSA-8983432	Interleukin-15 signaling
R-HSA-8984722	Interleukin-35 Signalling
R-HSA-8985947	Interleukin-9 signaling
R-HSA-9008059	Interleukin-37 signaling
R-HSA-9020933	Interleukin-23 signaling
R-HSA-9020956	Interleukin-27 signaling
R-HSA-9020958	Interleukin-21 signaling
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9670439	Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants
R-HSA-9673767	Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants
R-HSA-9673770	Signaling by PDGFRA extracellular domain mutants
R-HSA-9674555	Signaling by CSF3 (G-CSF)

MSigDB gene sets: 1352 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, PID_HDAC_CLASSI_PATHWAY, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, REACTOME_INTERLEUKIN_6_SIGNALING, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_BEHAVIOR, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_MYELOID_CELL_HOMEOSTASIS

GO Biological Process (104): negative regulation of transcription by RNA polymerase II (GO:0000122), temperature homeostasis (GO:0001659), response to hypoxia (GO:0001666), eye photoreceptor cell differentiation (GO:0001754), response to ischemia (GO:0002931), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), protein import into nucleus (GO:0006606), defense response (GO:0006952), acute-phase response (GO:0006953), inflammatory response (GO:0006954), signal transduction (GO:0007165), transforming growth factor beta receptor signaling pathway (GO:0007179), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), nervous system development (GO:0007399), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), negative regulation of autophagy (GO:0010507), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of hydrogen peroxide biosynthetic process (GO:0010730), cytokine-mediated signaling pathway (GO:0019221), cell differentiation (GO:0030154), positive regulation of cell migration (GO:0030335), intracellular receptor signaling pathway (GO:0030522), response to estradiol (GO:0032355), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), cellular response to hormone stimulus (GO:0032870), leptin-mediated signaling pathway (GO:0033210), somatic stem cell population maintenance (GO:0035019), interleukin-15-mediated signaling pathway (GO:0035723), interleukin-2-mediated signaling pathway (GO:0038110), interleukin-9-mediated signaling pathway (GO:0038113), interleukin-11-mediated signaling pathway (GO:0038154), interleukin-23-mediated signaling pathway (GO:0038155)

GO Molecular Function (26): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), RNA binding (GO:0003723), nuclear receptor activity (GO:0004879), signaling receptor binding (GO:0005102), protein kinase binding (GO:0019901), protein phosphatase binding (GO:0019903), chromatin DNA binding (GO:0031490), CCR5 chemokine receptor binding (GO:0031730), nuclear glucocorticoid receptor binding (GO:0035259), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein dimerization activity (GO:0046983), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), primary miRNA binding (GO:0070878), lncRNA binding (GO:0106222), DNA-binding transcription factor binding (GO:0140297), protein sequestering activity (GO:0140311), RNA sequestering activity (GO:0140610), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (13): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), mitochondrial inner membrane (GO:0005743), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), RNA polymerase II transcription regulator complex (GO:0090575), Schaffer collateral - CA1 synapse (GO:0098685), glutamatergic synapse (GO:0098978), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signaling by Interleukins	4
Signaling by Receptor Tyrosine Kinases	2
Interleukin-6 family signaling	1
Intrinsic Pathway for Apoptosis	1
FGFR1 mutant receptor activation	1
Signaling by PDGF	1
Signaling by NTRK1 (TRKA)	1
Cellular Senescence	1
Signal Transduction	1
Transcriptional regulation of pluripotent stem cells	1
Chaperonin-mediated protein folding	1
Developmental Biology	1
Signaling by PTK6	1
Signaling by MET	1
Interleukin-2 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
response to stress	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
protein binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of gene expression	2
regulation of DNA-templated transcription	2
cellular process	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
nucleic acid binding	2
synapse	2
negative regulation of DNA-templated transcription	1
multicellular organismal-level homeostasis	1
response to decreased oxygen levels	1
photoreceptor cell differentiation	1
eye morphogenesis	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
acute inflammatory response	1
defense response	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell surface receptor signaling pathway via STAT	1
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
positive regulation of cytokine production	1

Protein interactions and networks

STRING

8628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAT3	JAK2	O60674	999
STAT3	JAK1	P23458	999
STAT3	SRC	P12931	996
STAT3	JUN	P05412	994
STAT3	EP300	Q09472	992
STAT3	PIAS3	Q9Y6X2	988
STAT3	EGFR	P00533	986
STAT3	FOS	P01100	985
STAT3	STAT1	P42224	982
STAT3	STAT5A	P42229	974
STAT3	TP53	P04637	970
STAT3	STAT5B	P51692	968
STAT3	CD274	Q9NZQ7	968
STAT3	IL10RA	Q13651	967
STAT3	JAK3	P52333	967

IntAct

580 interactions, top by confidence:

A	B	Type	Score
SYK	STAT3	psi-mi:“MI:0915”(physical association)	0.870
STAT3	SYK	psi-mi:“MI:0915”(physical association)	0.870
STAT3	STAT3	psi-mi:“MI:0915”(physical association)	0.840
STAT3	STAT3	psi-mi:“MI:0914”(association)	0.840
BLK	STAT3	psi-mi:“MI:0915”(physical association)	0.830
BMX	STAT3	psi-mi:“MI:0915”(physical association)	0.830
STAT3	BLK	psi-mi:“MI:0915”(physical association)	0.830
STAT3		psi-mi:“MI:0914”(association)	0.730
SRC	LYN	psi-mi:“MI:0914”(association)	0.670
SP1	STAT3	psi-mi:“MI:0915”(physical association)	0.650
SP1	STAT3	psi-mi:“MI:2364”(proximity)	0.650
PAG1	LYN	psi-mi:“MI:0914”(association)	0.640
GADD45GIP1	STAT3	psi-mi:“MI:0915”(physical association)	0.630
SRI	STAT3	psi-mi:“MI:0915”(physical association)	0.630
LASP1	STAT3	psi-mi:“MI:0915”(physical association)	0.620
STAT3	LASP1	psi-mi:“MI:0915”(physical association)	0.620
STAT3	CCT3	psi-mi:“MI:0407”(direct interaction)	0.590

BioGRID (900): STAT3 (Two-hybrid), STAT3 (Affinity Capture-Western), STAT3 (Affinity Capture-Western), STAT3 (Two-hybrid), STAT3 (Two-hybrid), STAT3 (Two-hybrid), SYK (Two-hybrid), STAT3 (Affinity Capture-RNA), STAT3 (Affinity Capture-RNA), STAT3 (Affinity Capture-RNA), STAT3 (Affinity Capture-Western), NFKB2 (Affinity Capture-Western), STAT3 (Two-hybrid), STAT3 (Affinity Capture-MS), STAT3 (Affinity Capture-MS)

ESM2 similar proteins: A2A690, A2AWA9, A2RSQ0, A6QL63, F1LTE0, G3V7Q0, O60941, O70585, P40763, P42224, P42227, P42229, P42230, P42231, P52631, P52632, P84060, Q148V7, Q4V8I4, Q5R372, Q5R8N4, Q5RCW6, Q5ZJ17, Q62771, Q62784, Q6DFZ1, Q6DV79, Q6GQW0, Q6IQ26, Q6PAL8, Q6ZPY2, Q6ZUT9, Q7Z3J2, Q8BIK4, Q8CIQ7, Q8IZD9, Q8N122, Q8NFG4, Q92538, Q95115

Diamond homologs: O02799, P40763, P42224, P42225, P42227, P42228, P52630, P52631, P61635, Q14765, Q19S50, Q6DV79, Q764M5, Q7ZXK3, Q9PVX8, Q9WVL2, P42229, P42230, P42231, P42232, P51692, P52632, Q62771, Q95115, Q9TUM3, Q9TUZ0, Q9TUZ1, B5X561, Q24151, Q54BD4, O00910, Q70GP4, P42226, P52633, Q61AP6, Q7QDU4, Q9NAD6

SIGNOR signaling

166 interactions.

A	Effect	B	Mechanism
RPS6KA5	up-regulates	STAT3	phosphorylation
MAPK3	up-regulates	STAT3	phosphorylation
EGFR	“up-regulates activity”	STAT3	phosphorylation
ALK	up-regulates	STAT3	binding
CDK5	up-regulates	STAT3	phosphorylation
PIAS3	down-regulates	STAT3	sumoylation
IRAK1	up-regulates	STAT3	phosphorylation
IL21R	up-regulates	STAT3
PTPN1	down-regulates	STAT3	dephosphorylation
PRKCD	up-regulates	STAT3	phosphorylation
PRKCE	up-regulates	STAT3	phosphorylation
MTOR	up-regulates	STAT3	phosphorylation
MAPK14	up-regulates	STAT3	phosphorylation
NLK	up-regulates	STAT3	phosphorylation
PTPN6	down-regulates	STAT3	dephosphorylation
MAPK9	up-regulates	STAT3	phosphorylation
PTPRD	down-regulates	STAT3	dephosphorylation
JAK1	“up-regulates activity”	STAT3	phosphorylation
STAT3	“form complex”	SP1/STAT3	binding
S3I-201	down-regulates	STAT3	“chemical inhibition”
PKM	up-regulates	STAT3	phosphorylation
MAPK8	“up-regulates activity”	STAT3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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 phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	8	55.4×	5e-10
Regulation of signaling by CBL	6	39.7×	7e-07
Signaling by SCF-KIT	9	29.8×	4e-09
Interleukin-3, Interleukin-5 and GM-CSF signaling	7	29.6×	4e-07
Downstream signal transduction	5	25.4×	7e-05
GPVI-mediated activation cascade	6	24.7×	1e-05
Signaling by CSF1 (M-CSF) in myeloid cells	5	23.1×	1e-04
VEGFA-VEGFR2 Pathway	6	11.1×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
B cell receptor signaling pathway	6	25.6×	1e-04
cell surface receptor protein tyrosine kinase signaling pathway	6	11.1×	3e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	6.7×	4e-03
transcription by RNA polymerase II	8	6.0×	7e-03
protein phosphorylation	8	5.8×	8e-03
intracellular signal transduction	13	5.3×	3e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — DLBCLNOS, LNM, MLYM, NHL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	47
Uncertain significance	316
Likely benign	308
Benign	87

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1005984	NM_139276.3(STAT3):c.2141C>T (p.Thr714Ile)	Pathogenic
1039785	NM_139276.3(STAT3):c.1228C>T (p.His410Tyr)	Pathogenic
1068485	NM_139276.3(STAT3):c.1859C>G (p.Thr620Ser)	Pathogenic
1398166	NM_139276.3(STAT3):c.1110-2A>G	Pathogenic
1429110	NM_139276.3(STAT3):c.2116C>A (p.Leu706Met)	Pathogenic
1429145	NM_139276.3(STAT3):c.1915C>G (p.Pro639Ala)	Pathogenic
144030	NM_139276.3(STAT3):c.1175A>G (p.Lys392Arg)	Pathogenic
144031	NM_139276.3(STAT3):c.1938C>G (p.Asn646Lys)	Pathogenic
144032	NM_139276.3(STAT3):c.1974G>C (p.Lys658Asn)	Pathogenic
1705748	NM_139276.3(STAT3):c.1910T>C (p.Val637Ala)	Pathogenic
1800571	NM_139276.3(STAT3):c.988C>T (p.Pro330Ser)	Pathogenic
1804642	NM_139276.3(STAT3):c.985A>G (p.Met329Val)	Pathogenic
1804643	NM_139276.3(STAT3):c.1858A>G (p.Thr620Ala)	Pathogenic
18303	NM_139276.3(STAT3):c.1384GTG[1] (p.Val463del)	Pathogenic
18304	NM_139276.3(STAT3):c.1144C>T (p.Arg382Trp)	Pathogenic
18305	NM_139276.3(STAT3):c.1145G>A (p.Arg382Gln)	Pathogenic
18306	NM_139276.3(STAT3):c.1268G>A (p.Arg423Gln)	Pathogenic
18307	NM_139276.3(STAT3):c.1145G>T (p.Arg382Leu)	Pathogenic
18308	NM_139276.3(STAT3):c.1909G>A (p.Val637Met)	Pathogenic
2099076	NM_139276.3(STAT3):c.1145G>C (p.Arg382Pro)	Pathogenic
2138013	NM_139276.3(STAT3):c.1915C>A (p.Pro639Thr)	Pathogenic
2138015	NM_139276.3(STAT3):c.1907C>A (p.Ser636Tyr)	Pathogenic
2138016	NM_139276.3(STAT3):c.1865C>T (p.Thr622Ile)	Pathogenic
2169593	NM_139276.3(STAT3):c.1934T>A (p.Leu645Gln)	Pathogenic
224843	NM_139276.3(STAT3):c.1032G>C (p.Gln344His)	Pathogenic
224846	NM_139276.3(STAT3):c.454C>T (p.Arg152Trp)	Pathogenic
224847	NM_139276.3(STAT3):c.1057G>T (p.Val353Phe)	Pathogenic
224848	NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)	Pathogenic
224849	NM_139276.3(STAT3):c.1260T>G (p.Asn420Lys)	Pathogenic
224850	NM_139276.3(STAT3):c.2107G>A (p.Ala703Thr)	Pathogenic

SpliceAI

3192 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42315796:GGACT:G	acceptor_gain	1.0000
17:42315797:GACT:G	acceptor_gain	1.0000
17:42315799:CT:C	acceptor_gain	1.0000
17:42315801:C:CC	acceptor_gain	1.0000
17:42315801:C:CG	acceptor_loss	1.0000
17:42316788:CCAAA:C	donor_gain	1.0000
17:42317180:A:AC	donor_gain	1.0000
17:42317181:C:CC	donor_gain	1.0000
17:42322280:ACTAC:A	donor_loss	1.0000
17:42322281:CTACC:C	donor_loss	1.0000
17:42322282:TACCT:T	donor_loss	1.0000
17:42322283:ACCT:A	donor_loss	1.0000
17:42322284:C:CT	donor_loss	1.0000
17:42322331:T:A	donor_gain	1.0000
17:42322490:CTTAC:C	acceptor_gain	1.0000
17:42322491:TTAC:T	acceptor_gain	1.0000
17:42322493:AC:A	acceptor_gain	1.0000
17:42322494:CC:C	acceptor_gain	1.0000
17:42322499:C:CT	acceptor_gain	1.0000
17:42322502:A:T	acceptor_gain	1.0000
17:42322507:A:C	acceptor_gain	1.0000
17:42322997:C:CA	donor_gain	1.0000
17:42322998:CCTTA:C	donor_loss	1.0000
17:42322999:CTTA:C	donor_loss	1.0000
17:42323000:TTA:T	donor_loss	1.0000
17:42323001:TA:T	donor_loss	1.0000
17:42323002:A:AC	donor_gain	1.0000
17:42323003:C:CC	donor_gain	1.0000
17:42323003:C:CG	donor_loss	1.0000
17:42323003:CCG:C	donor_gain	1.0000

AlphaMissense

5104 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42322335:A:G	F683S	1.000
17:42322346:C:A	K679N	1.000
17:42322346:C:G	K679N	1.000
17:42322365:A:G	L673P	1.000
17:42322365:A:T	L673H	1.000
17:42322374:A:G	L670P	1.000
17:42322374:A:T	L670Q	1.000
17:42322377:G:T	P669Q	1.000
17:42322449:A:G	L645P	1.000
17:42322465:A:C	Y640D	1.000
17:42322467:G:T	P639Q	1.000
17:42323025:A:G	W623R	1.000
17:42323025:A:T	W623R	1.000
17:42323042:C:T	G617E	1.000
17:42323043:C:G	G617R	1.000
17:42323043:C:T	G617R	1.000
17:42323059:A:C	S611R	1.000
17:42323059:A:T	S611R	1.000
17:42323060:C:A	S611I	1.000
17:42323060:C:T	S611N	1.000
17:42323061:T:G	S611R	1.000
17:42323062:G:C	F610L	1.000
17:42323062:G:T	F610L	1.000
17:42323063:A:C	F610C	1.000
17:42323063:A:G	F610S	1.000
17:42323064:A:G	F610L	1.000
17:42323065:T:A	R609S	1.000
17:42323065:T:G	R609S	1.000
17:42323066:C:A	R609I	1.000
17:42323066:C:G	R609T	1.000

dbSNP variants (sampled 300 via entrez): RS1000025502 (17:42324300 C>T), RS1000056631 (17:42324523 C>A), RS1000061973 (17:42332625 T>C), RS1000077009 (17:42371574 G>A), RS1000196515 (17:42377781 C>A), RS1000248074 (17:42330955 A>T), RS1000248268 (17:42376800 C>A,T), RS1000250544 (17:42378035 G>A), RS1000316886 (17:42389589 A>G), RS1000322705 (17:42344254 C>T), RS1000379861 (17:42338927 T>C,G), RS1000390258 (17:42335858 G>A), RS1000396122 (17:42383485 G>A), RS1000474706 (17:42322937 G>A,C), RS1000532410 (17:42376086 G>A)

Disease associations

OMIM: gene MIM:102582 | disease phenotypes: MIM:146840, MIM:147060, MIM:615952

GenCC curated gene-disease

Disease	Classification	Inheritance
hyper-IgE recurrent infection syndrome 1, autosomal dominant	Strong	Autosomal dominant
STAT3-related early-onset multisystem autoimmune disease	Strong	Autosomal dominant
permanent neonatal diabetes mellitus	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
STAT3-related early-onset multisystem autoimmune disease	Definitive	AD
hyper-IgE recurrent infection syndrome 1, autosomal dominant	Definitive	AD

Mondo (5): hyper-IgE recurrent infection syndrome 1, autosomal dominant (MONDO:0007818), STAT3-related early-onset multisystem autoimmune disease (MONDO:0014414), hyper-IgE syndrome (MONDO:0018037), diffuse large B-cell lymphoma (MONDO:0018905), permanent neonatal diabetes mellitus (MONDO:0100164)

Orphanet (4): Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency (Orphanet:2314), STAT3-related early-onset multisystem autoimmune disease (Orphanet:438159), Hyper-IgE syndrome (Orphanet:331223), Diffuse large B-cell lymphoma (Orphanet:544)

HPO phenotypes

177 total (30 of 177 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000124	Renal tubular dysfunction
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000225	Gingival bleeding
HP:0000230	Gingivitis
HP:0000271	Abnormality of the face
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000421	Epistaxis
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000488	Retinopathy
HP:0000490	Deeply set eye
HP:0000684	Delayed eruption of teeth
HP:0000703	Dentinogenesis imperfecta
HP:0000790	Hematuria
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty
HP:0000857	Neonatal insulin-dependent diabetes mellitus
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000964	Eczematoid dermatitis
HP:0000967	Petechiae

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST000207_10	Crohn’s disease	7.000000e-12
GCST000593_2	Multiple sclerosis	3.000000e-10
GCST000879_46	Crohn’s disease	3.000000e-08
GCST001198_35	Multiple sclerosis	2.000000e-10
GCST001341_5	Multiple sclerosis	4.000000e-08
GCST001725_55	Inflammatory bowel disease	6.000000e-22
GCST001785_4	Crohn’s disease	2.000000e-15
GCST002874_17	Psoriasis	6.000000e-07
GCST003184_10	Atopic dermatitis	1.000000e-07
GCST003184_18	Atopic dermatitis	3.000000e-06
GCST003602_13	Inflammatory bowel disease	2.000000e-09
GCST004131_42	Inflammatory bowel disease	2.000000e-17
GCST004132_58	Crohn’s disease	2.000000e-11
GCST004133_53	Ulcerative colitis	1.000000e-10
GCST004602_293	Mean corpuscular volume	7.000000e-10
GCST004861_21	Itch intensity from mosquito bite	8.000000e-10
GCST004862_106	Itch intensity from mosquito bite adjusted by bite size	1.000000e-07
GCST005527_33	Psoriasis	5.000000e-09
GCST005531_63	Multiple sclerosis	4.000000e-20
GCST005537_32	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	2.000000e-15
GCST005752_60	Systemic lupus erythematosus	3.000000e-06
GCST006867_139	Type 2 diabetes	2.000000e-09
GCST007268_62	Diastolic blood pressure	3.000000e-08
GCST008572_11	Composite immunoglobulin trait (IgA/IgG)	3.000000e-06
GCST008731_3	Inflammatory bowel disease	9.000000e-06
GCST009597_226	Multiple sclerosis	2.000000e-28
GCST010124_4	Crohn’s disease or systemic sclerosis	3.000000e-08
GCST010243_68	Apolipoprotein B levels	4.000000e-08
GCST010571_68	Autoimmune thyroid disease	1.000000e-12
GCST011365_153	Myocardial infarction	3.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0006336	diastolic blood pressure
EFO:0004615	apolipoprotein B measurement
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
C563425	Diabetes Mellitus, Permanent Neonatal (supp.)
C567925	Hyper-Ige Recurrent Infection Syndrome, Autosomal Dominant (supp.)
C564135	Immunodeficiency with Defective Leukocyte and Lymphocyte Function and with Response to Histamine-1 Antagonist (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL4026 (SINGLE PROTEIN), CHEMBL4296101 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523691 (PROTEIN-PROTEIN INTERACTION), CHEMBL5482983 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

18 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 294,245 (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
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1401	NITAZOXANIDE	4	9,504
CHEMBL1448	NICLOSAMIDE	4	14,322
CHEMBL1751	DIGOXIN	4	67,342
CHEMBL2105759	BARICITINIB	4	6,741
CHEMBL254219	DIGITOXIN	4	16,757
CHEMBL4435170	DEUCRAVACITINIB	4	679
CHEMBL140	CURCUMIN	3	93,882
CHEMBL1762621	BARDOXOLONE METHYL	3	1,032
CHEMBL244888	NIFUROXAZIDE	3	1,459
CHEMBL4297507	DELGOCITINIB	3	767
CHEMBL603469	LESTAURTINIB	3
CHEMBL64130	NAPABUCASIN	3	909
CHEMBL1096927	LEVOMENOL	2	31,030
CHEMBL1231124	AZD-1480	2	1,576
CHEMBL1923234	WP 1066	2	374
CHEMBL3392776	C-188-9	2	178
CHEMBL44	GENISTEIN	2	44,212

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4796793	Efficacy	3	interferons	Renal Cell Carcinoma

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1053004	STAT3		0.00	0
rs1053005	STAT3		0.00	0
rs1053023	STAT3		0.00	0
rs4796793	STAT3	3	2.75	1	interferons

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — STAT transcription factors

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
SD-91	Binding	7.55	pKd
SD-36	Inhibition	7.36	pKd
LLL12	Inhibition	7.01	pIC50
STAT3 inhibitor 8q	Binding	6.96	pKd
YZ-35	Inhibition	6.72	pKd
compound 6f [PMID: 35476936]	Binding	6.34	pKd
compound 8u [PMID: 31999451]	Binding	6.28	pKd
WP1066	Inhibition	5.75	pIC50

Binding affinities (BindingDB)

173 measured of 511 human assays (514 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5,7-dihydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one	EC50	0.00334 nM
4-(3,4-dihydro-2H-quinolin-1-yl)-[1,2,4]triazolo[4,3-a]quinoxaline	EC50	0.00483 nM
7-amino-3-phenyl-6-pyrazolo[1,5-a]pyrimidinecarboxylic acid ethyl ester	EC50	356 nM
1-(1-acetyl-2,3-dihydroindol-5-yl)-4-hydroxy-3-pyrazolecarboxylic acid methyl ester	EC50	610 nM
BDBM50556935	IC50	978 nM	US-11299480: 2-arylsulfonamido-N-arylacetamide derivatized STAT3 inhibitors
1-(3-chlorophenyl)-3-(2-pyridin-3-ylpyrimidin-4-yl)urea	EC50	1110 nM
2-[(3,5-dimethyl-1,2-oxazol-4-yl)methylsulfanyl]-1-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethanone	IC50	1120 nM
MLS000569713	EC50	1260 nM
(2R)-N-[(4-cyclohexylphenyl)methyl]-1-(2,3,4,5,6-pentafluorophenyl)sulfonyl-N-[4-(2H-tetrazol-5-yl)phenyl]azetidine-2-carboxamide	IC50	1360 nM	US-11299480: 2-arylsulfonamido-N-arylacetamide derivatized STAT3 inhibitors
BDBM50556937	IC50	1460 nM	US-11299480: 2-arylsulfonamido-N-arylacetamide derivatized STAT3 inhibitors
2-[(3-cyano-6-pyridin-4-yl-2-pyridinyl)thio]acetic acid ethyl ester	EC50	1710 nM
(2R)-N-[(4-cyclohexylphenyl)methyl]-N-(1-oxo-2H-phthalazin-6-yl)-1-(2,3,4,5,6-pentafluorophenyl)sulfonylazetidine-2-carboxamide	IC50	1800 nM	US-11299480: 2-arylsulfonamido-N-arylacetamide derivatized STAT3 inhibitors
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[[2-(trifluoromethyl)phenyl]methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	1800 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
MLS000729575	EC50	2000 nM
BDBM50556945	IC50	2350 nM	US-11299480: 2-arylsulfonamido-N-arylacetamide derivatized STAT3 inhibitors
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-(naphthalen-2-ylmethyl)amino]acetyl]amino]-2-hydroxybenzoic acid	KI	2500 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[(3-nitrophenyl)methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	2500 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(3-methylphenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	2600 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(2-methylphenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	2600 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[[2-[(3-chlorophenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]-[(4-cyclohexylphenyl)methyl]amino]-2-hydroxybenzoic acid	KI	3000 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[[2-[(4-chlorophenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]-[(4-cyclohexylphenyl)methyl]amino]-2-hydroxybenzoic acid	KI	3100 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
1-[[5-[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]sulfanyl-1,3,4-oxadiazol-2-yl]methyl]azepan-2-one	IC50	3460 nM
4-[4-(4-keto-2-thioxo-1H-quinazolin-3-yl)benzoyl]piperazine-1-carboxylic acid ethyl ester	IC50	3470 nM
2-(4-methylphenyl)-5-pyridin-4-yl-4H-benzo[i][1,3,4]benzotriazepine	IC50	3520 nM
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[[2-(trifluoromethoxy)phenyl]methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	3600 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-ethoxycarbonylphenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	3800 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-fluorophenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	3800 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[[3-(trifluoromethoxy)phenyl]methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	4000 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
3-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrazol-3-yl)-7-butan-2-yl-6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine	IC50	4100 nM	US-10618914: 6-aryl-7-substituted-3-(1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-B][1,3,4]thiadiazines as inhibitors of the STAT3 pathway with anti-proliferative activity
3-[[4-(2-fluorophenyl)-1,3-thiazol-2-yl]methyl]-2-[(4-methylpiperazin-1-yl)methyl]quinazolin-4-one	IC50	4240 nM
4-[(4-cyclohexylphenyl)methyl-[2-[(4-isocyanophenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	4300 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
(E)-2-(1H-Benzoimidazol-2-yl)-3-(5-morpholin-4-yl-furan-2-yl)-acrylonitrile	EC50	4320 nM
2-[(7-hydroxy-2-keto-chromen-4-yl)methylthio]-1H-quinazolin-4-one	IC50	4360 nM
4-[(4-cyclohexylphenyl)methyl-[2-[(3-fluorophenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	4400 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
Isonicotinic acid N’-(1,3-diethyl-4,6-dioxo-2-thioxo-tetrahydro-pyrimidin-5-ylidenemethyl)-hydrazide	IC50	4420 nM
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[(2,3,4,5,6-pentafluorophenyl)methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	4500 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[[4-(trifluoromethyl)phenyl]methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	4600 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[[4-(trifluoromethylsulfanyl)phenyl]methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	4800 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[(2-nitrophenyl)methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	5000 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
7-butan-2-yl-6-(4-methoxyphenyl)-3-(5-phenylpyrazolidin-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine	IC50	5100 nM	US-10618914: 6-aryl-7-substituted-3-(1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-B][1,3,4]thiadiazines as inhibitors of the STAT3 pathway with anti-proliferative activity
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[[3-(trifluoromethyl)phenyl]methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	5100 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
3-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrazol-3-yl)-6-(4-methoxyphenyl)-7-(2-methylpropyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine	IC50	5140 nM	US-10618914: 6-aryl-7-substituted-3-(1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-B][1,3,4]thiadiazines as inhibitors of the STAT3 pathway with anti-proliferative activity
(4-methoxy-1,3-benzothiazol-2-yl)-[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]amine	IC50	5160 nM
3-(3,4-dimethylphenyl)-4-keto-phthalazine-1-carboxylic acid	IC50	5200 nM
4-[(4-cyclohexylphenyl)methyl-[2-[(2-fluorophenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	5300 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	5500 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methylphenyl)sulfonyl-[(4-nitrophenyl)methyl]amino]acetyl]amino]-2-hydroxybenzoic acid	KI	5500 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
(2E)-2-(1,3-benzothiazol-2-yl)-2-(2-ketoindolin-3-ylidene)acetonitrile	IC50	5660 nM
(7R)-3-[5-(4-chlorophenyl)pyrazolidin-3-yl]-6-(4-methoxyphenyl)-7-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine	IC50	5720 nM	US-10618914: 6-aryl-7-substituted-3-(1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-B][1,3,4]thiadiazines as inhibitors of the STAT3 pathway with anti-proliferative activity
4-[(4-cyclohexylphenyl)methyl-[2-[(4-methoxycarbonylphenyl)methyl-(4-methylphenyl)sulfonylamino]acetyl]amino]-2-hydroxybenzoic acid	KI	5800 nM	US-10196373: Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein

ChEMBL bioactivities

1169 potent at pChembl≥5 of 1666 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.98	EC50	1.04	nM	CHEMBL1389016
8.66	EC50	2.19	nM	CHEMBL1449962
8.62	IC50	2.4	nM	CHEMBL5437070
8.34	EC50	4.55	nM	CHEMBL1703740
8.33	Kd	4.7	nM	C-188-9
8.29	Ki	5.1	nM	CHEMBL4776801
8.28	IC50	5.3	nM	CHEMBL5177956
8.23	IC50	5.9	nM	CHEMBL5209107
8.23	IC50	5.9	nM	CHEMBL5439447
8.22	Ki	6	nM	CHEMBL6167410
8.15	Ki	7	nM	CHEMBL4560429
8.15	IC50	7	nM	CHEMBL5405538
8.09	EC50	8.15	nM	CHEMBL1430610
8.05	IC50	9	nM	CHEMBL5433451
8.00	IC50	10	nM	LESTAURTINIB
7.93	Ki	11.7	nM	CHEMBL4452527
7.92	Ki	12	nM	CHEMBL4471887
7.89	IC50	13	nM	CHEMBL5404765
7.89	IC50	13	nM	CHEMBL4469750
7.88	IC50	13.1	nM	CHEMBL5201151
7.85	Ki	14	nM	CHEMBL4575382
7.85	Ki	14	nM	CHEMBL4443339
7.85	Ki	14	nM	CHEMBL4515406
7.82	IC50	15	nM	CHEMBL4444178
7.77	IC50	17	nM	CHEMBL5395308
7.75	IC50	18	nM	DELGOCITINIB
7.72	IC50	19	nM	CHEMBL6144023
7.70	IC50	19.8	nM	CHEMBL5171007
7.70	IC50	20	nM	BARICITINIB
7.67	Kd	21.3	nM	CHEMBL5177956
7.65	IC50	22.3	nM	CHEMBL5178622
7.65	IC50	22.57	nM	CHEMBL5558267
7.64	IC50	23	nM	AZD-1480
7.60	Ki	25	nM	CHEMBL4571181
7.56	IC50	27.8	nM	CHEMBL5176684
7.55	Kd	28	nM	CHEMBL4776801
7.55	IC50	28.1	nM	CHEMBL5189135
7.55	IC50	28	nM	CHEMBL5419627
7.54	Kd	28.81	nM	CHEMBL4868479
7.54	IC50	29	nM	CHEMBL5428659
7.53	IC50	29.43	nM	CHEMBL5555159
7.52	IC50	30.5	nM	CHEMBL5184385
7.49	IC50	32.3	nM	CHEMBL5176948
7.48	Ki	33	nM	CHEMBL4443240
7.48	IC50	33	nM	DELGOCITINIB
7.48	Ki	33	nM	CHEMBL1774957
7.47	Kd	33.61	nM	CHEMBL5175648
7.46	IC50	35	nM	CHEMBL5279856
7.45	IC50	35.7	nM	CHEMBL5201419
7.43	IC50	37.4	nM	CHEMBL5182844

PubChem BioAssay actives

762 with measured affinity, of 3167 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
methyl (1S,2R,3R,6R,8R,13S,14S,15R,16S,17S)-3-[(E)-4-acetyloxy-3,4-dimethylpent-2-enoyl]oxy-10,15,16-trihydroxy-9,13-dimethyl-4,11-dioxo-5,18-dioxapentacyclo[12.4.0.01,6.02,17.08,13]octadec-9-ene-17-carboxylate	1924817: Inhibition of STAT3 (unknown origin) DNA binding activity by EMSA	ic50	<0.0001	uM
methyl (1R,2S,3R,6R,8R,13S,14R,15R,16S,17S)-3-[(E)-4-acetyloxy-3,4-dimethylpent-2-enoyl]oxy-10,15,16-trihydroxy-9,13-dimethyl-4,11-dioxo-5,18-dioxapentacyclo[12.5.0.01,6.02,17.08,13]nonadec-9-ene-17-carboxylate	2073769: Inhibition of STAT3 (unknown origin)	ic50	<0.0001	uM
6-(cyclopropanecarbonylamino)-4-[2-methoxy-3-[5-[2-(trifluoromethyl)-3-pyridinyl]pyrimidin-2-yl]anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide	2029534: Inhibition of IL-23 induced STAT3 phosphorylation in human Jurkat cells incubated for 30 mins by microplate reader analysis	ic50	0.0024	uM
N-[4-hydroxy-3-(2-hydroxynaphthalen-1-yl)naphthalen-1-yl]-4-methoxybenzenesulfonamide	1930274: Binding affinity to STAT3 (127 to 722 residues) (unknown origin) by microscale thermophoresis analysis	kd	0.0047	uM
[2-[[(5S,8S,10aR)-8-[[(2S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl]carbamoyl]-3-[8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oct-7-ynoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indole-5-carbonyl]phosphonic acid	1710337: Binding affinity to recombinant STAT3 (unknown origin) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0051	uM
[6-[5-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1-methylindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0053	uM
[6-[5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1-methylindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0059	uM
6-[[5-(3-hydroxyazetidin-1-yl)-2-pyridinyl]amino]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide	2029533: Inhibition of IL-23 induced STAT3 phosphorylation in human KIT225 cells by AlphaLISA assay	ic50	0.0059	uM
5-(3,4-dihydro-2H-chromen-8-ylamino)-7-(methylamino)-N-[(3R)-1-methyl-2-oxopyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	2029533: Inhibition of IL-23 induced STAT3 phosphorylation in human KIT225 cells by AlphaLISA assay	ic50	0.0070	uM
[[2-[[(3S,6S,10aS)-3-[[(2S)-5-amino-1-(benzylamino)-1,5-dioxopentan-2-yl]carbamoyl]-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocin-6-yl]carbamoyl]-1H-indol-5-yl]-difluoromethyl]phosphonic acid	1559038: Binding affinity to recombinant human His/SUMO-tagged STAT3 (127 to 688 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	ki	0.0070	uM
5-(2-methoxyanilino)-7-(methylamino)-N-[(3R)-1-methyl-2-oxopyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	2029533: Inhibition of IL-23 induced STAT3 phosphorylation in human KIT225 cells by AlphaLISA assay	ic50	0.0090	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	1993936: Inhibition of STAT3 phosphorylation in HEL 92.1.7 cells incubated for 24 hrs by Western blot analysis	ic50	0.0100	uM
[[2-[[(5S,8S,10aR)-8-[[(2S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl]carbamoyl]-3-[8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oct-7-ynoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indol-5-yl]-difluoromethyl]phosphonic acid	1710337: Binding affinity to recombinant STAT3 (unknown origin) assessed as inhibition constant incubated for 1 hr by fluorescence polarization assay	ki	0.0117	uM
[[2-[[(5S,8S,10aR)-8-[[(2S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl]carbamoyl]-3-methyl-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indol-5-yl]-difluoromethyl]phosphonic acid	1559038: Binding affinity to recombinant human His/SUMO-tagged STAT3 (127 to 688 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	ki	0.0120	uM
3-[3-[5-methyl-2-[(3-methyl-1,2-thiazol-5-yl)amino]pyrimidin-4-yl]-3,9-diazabicyclo[3.3.1]nonan-9-yl]propanenitrile	1981406: Inhibition of IL-6 stimulated STAT3 phosphorylation in HEK-Blue IL-6 cells incubated for 20 to 24 hrs by QUANTI-Blue assay	ic50	0.0130	uM
6-[(5-cyano-2-pyridinyl)amino]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-methylpyridine-3-carboxamide	2011257: Inhibition of IL-23 induced STAT3 phosphorylation in human KIT225 cells by AlphaLISA assay	ic50	0.0130	uM
[6-[5-[3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1-methylindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0131	uM
[[2-[[(5S,8S,10aR)-3-acetyl-8-[[(2S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl]carbamoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indol-5-yl]-difluoromethyl]phosphonic acid	1559038: Binding affinity to recombinant human His/SUMO-tagged STAT3 (127 to 688 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	ki	0.0140	uM
[[2-[[(5S,8S,10aR)-8-[[(2S)-5-amino-1-(benzylamino)-1,5-dioxopentan-2-yl]carbamoyl]-3-methyl-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indol-5-yl]-difluoromethyl]phosphonic acid	1559038: Binding affinity to recombinant human His/SUMO-tagged STAT3 (127 to 688 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	ki	0.0140	uM
[[2-[[(5S,8S,10aR)-3-acetyl-8-[[(2S)-5-amino-1-(benzylamino)-1,5-dioxopentan-2-yl]carbamoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indol-5-yl]-difluoromethyl]phosphonic acid	1559038: Binding affinity to recombinant human His/SUMO-tagged STAT3 (127 to 688 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	ki	0.0140	uM
6-(cyclopropanecarbonylamino)-4-(2-methylsulfonylanilino)-N-(trideuteriomethyl)pyridazine-3-carboxamide	2011257: Inhibition of IL-23 induced STAT3 phosphorylation in human KIT225 cells by AlphaLISA assay	ic50	0.0150	uM
(3R)-3-cyclopentyl-3-[4-[5-methyl-2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]pyrazol-1-yl]propanenitrile	1981406: Inhibition of IL-6 stimulated STAT3 phosphorylation in HEK-Blue IL-6 cells incubated for 20 to 24 hrs by QUANTI-Blue assay	ic50	0.0170	uM
3-[(3S,4R)-3-methyl-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile	1941947: Inhibition of IFN-alpha induced STAT3 phosphorylation in human PBMC preincubated with compound for 30 mins followed by IFN-alpha stimulation and measured after 15 mins by flow cytometric analysis	ic50	0.0180	uM
[6-[5-[3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1-methylindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0198	uM
Baricitinib	1941916: Inhibition of IL-23 stimulated STAT3 production in human naive T cell preincubated with compound for 10 to 15 mins followed by IL-23 stimulation and measured after 15 mins by ELISA analysis	ic50	0.0200	uM
[1-methyl-6-[5-[3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxyindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0223	uM
3-methyl-4,8-dioxo-N-(3-pyrrolidin-1-ylpropyl)thieno[2,3-f][1,2]benzoxazole-6-carboxamide	2063810: Inhibition of leukemia inhibitory factor-induced STAT3 transcriptional activity in human HeLa cells expressing 4SIE pretreated for 1 hr followed by LIF stimulation and measured after 4 hrs by firefly luciferase assay	ic50	0.0226	uM
5-chloro-2-N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-4-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine	553167: Inhibition of Stat3 phosphorylation in human SET2 cells after 1 hr by Western blotting	ic50	0.0230	uM
[2-[[(3S,6S,10aS)-3-[[(2S)-5-amino-1-(benzylamino)-1,5-dioxopentan-2-yl]carbamoyl]-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocin-6-yl]carbamoyl]-1H-indol-5-yl] dihydrogen phosphate	1559038: Binding affinity to recombinant human His/SUMO-tagged STAT3 (127 to 688 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	ki	0.0250	uM
[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]-[4-[5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methanone	1856407: Inhibition of human recombinant STAT3 (127 to 722 residues) transcriptional activity expressed in HEK293T cells in presence of IL-6 by Dual-luciferase reporter gene assay	ic50	0.0278	uM
6-(azetidine-1-carbonylamino)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-methylpyridazine-3-carboxamide	2029533: Inhibition of IL-23 induced STAT3 phosphorylation in human KIT225 cells by AlphaLISA assay	ic50	0.0280	uM
[6-[5-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1-methylindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0281	uM
5-[[2-[(2R)-2-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-1-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1757423: Binding affinity to His-tagged STAT3-SH2 domain (127 to 722 residues) (unknown origin) by surface plasmon resonance analysis	kd	0.0288	uM
5-[(6-ethoxy-2-pyridinyl)amino]-7-(methylamino)-N-[(3R)-1-methyl-2-oxopyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	2029533: Inhibition of IL-23 induced STAT3 phosphorylation in human KIT225 cells by AlphaLISA assay	ic50	0.0290	uM
3-methyl-4,8-dioxo-N-(2-pyrrolidin-1-ylethyl)thieno[2,3-f][1,2]benzoxazole-6-carboxamide	2063810: Inhibition of leukemia inhibitory factor-induced STAT3 transcriptional activity in human HeLa cells expressing 4SIE pretreated for 1 hr followed by LIF stimulation and measured after 4 hrs by firefly luciferase assay	ic50	0.0294	uM
[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]-[6-[5-[3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1H-indol-2-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0305	uM
[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]-[4-[3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]-2-pyridinyl]methanone	1856407: Inhibition of human recombinant STAT3 (127 to 722 residues) transcriptional activity expressed in HEK293T cells in presence of IL-6 by Dual-luciferase reporter gene assay	ic50	0.0323	uM
[2-[[(5S,8S,10aR)-3-acetyl-8-[[(2S)-5-amino-1-(benzhydrylamino)-1,5-dioxopentan-2-yl]carbamoyl]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl]-1H-indol-5-yl] dihydrogen phosphate	1559038: Binding affinity to recombinant human His/SUMO-tagged STAT3 (127 to 688 residues) expressed in Escherichia coli Rosetta (DE3) incubated for 1 hr by fluorescence polarization assay	ki	0.0330	uM
[4-[(E)-4-[[(2S)-1-[(1R,2S,5S)-2-[[(2S)-5-amino-1-(benzylamino)-1,5-dioxopentan-2-yl]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-1-oxohexan-2-yl]amino]-4-oxobut-2-en-2-yl]phenyl] dihydrogen phosphate	596731: Binding affinity to SH2 domain of Stat3 by fluorescence polarization assay	ki	0.0330	uM
7-[4-[(E)-2-(3,5-dimethoxyphenyl)ethenyl]phenoxy]-N-hydroxyheptanamide	1898504: Binding affinity to recombinant GST tagged STAT3 (unknown origin) assessed as dissociation constant	kd	0.0336	uM
(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[[3-[[1,3-dimethyl-2-oxo-6-(3-propoxyphenoxy)benzimidazol-5-yl]sulfamoyl]benzoyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]hexanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1942758: Inhibition of STAT3 phosphorylation a in human MOLM16 cells	ic50	0.0350	uM
[6-[5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1-methylindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0357	uM
[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]-[6-[3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]-3-pyridinyl]methanone	1856407: Inhibition of human recombinant STAT3 (127 to 722 residues) transcriptional activity expressed in HEK293T cells in presence of IL-6 by Dual-luciferase reporter gene assay	ic50	0.0374	uM
3-[3-[5-methyl-2-[(3-methyl-1,2-thiazol-5-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]propanenitrile	1981406: Inhibition of IL-6 stimulated STAT3 phosphorylation in HEK-Blue IL-6 cells incubated for 20 to 24 hrs by QUANTI-Blue assay	ic50	0.0380	uM
3-methyl-4,8-dioxo-N-(3-piperidin-1-ylpropyl)thieno[2,3-f][1,2]benzoxazole-6-carboxamide	2063810: Inhibition of leukemia inhibitory factor-induced STAT3 transcriptional activity in human HeLa cells expressing 4SIE pretreated for 1 hr followed by LIF stimulation and measured after 4 hrs by firefly luciferase assay	ic50	0.0380	uM
[6-[5-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxy-1-methylindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0383	uM
[4-[(E)-4-[[(2S)-1-[(1R,2S,5S)-2-[2-(carbamoylamino)ethylcarbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobut-2-en-2-yl]phenyl] dihydrogen phosphate	596731: Binding affinity to SH2 domain of Stat3 by fluorescence polarization assay	ki	0.0390	uM
[1-methyl-6-[5-[3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxyindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0392	uM
[1-(2-methoxyethyl)-6-[5-[3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]pyrazin-2-yl]oxyindol-2-yl]-[4-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]piperazin-1-yl]methanone	1848365: Inhibition of STAT3 in human HEK293T cells assessed as inhibition of IL-6 stimulated STAT3 phosphorylation by dual-luciferase reporter assay	ic50	0.0399	uM
[4-[(4-bromophenyl)methyl]piperazin-1-yl]-[6-[3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]-3-pyridinyl]methanone	1856407: Inhibition of human recombinant STAT3 (127 to 722 residues) transcriptional activity expressed in HEK293T cells in presence of IL-6 by Dual-luciferase reporter gene assay	ic50	0.0402	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide	affects binding, affects cotreatment, decreases reaction, increases activity, increases phosphorylation (+6 more)	23
Resveratrol	increases phosphorylation, affects binding, affects cotreatment, decreases expression, decreases acetylation (+8 more)	23
sodium arsenite	affects localization, increases activity, affects binding, decreases phosphorylation, increases abundance (+8 more)	14
Acetylcysteine	increases activity, decreases activity, decreases phosphorylation, decreases reaction, increases phosphorylation (+1 more)	14
Arsenic Trioxide	decreases reaction, increases activity, increases phosphorylation, decreases expression, increases reaction (+6 more)	13
Niclosamide	increases reaction, decreases expression, decreases response to substance, decreases activity, decreases phosphorylation (+4 more)	12
Particulate Matter	decreases methylation, increases reaction, affects reaction, affects binding, affects expression (+5 more)	12
bisphenol A	increases response to substance, affects cotreatment, affects activity, increases activity, increases phosphorylation (+7 more)	11
tofacitinib	affects cotreatment, increases activity, decreases activity, decreases expression, decreases phosphorylation (+2 more)	11
Quercetin	increases phosphorylation, decreases activity, affects localization, increases reaction, decreases reaction (+4 more)	10
Arsenic	affects reaction, decreases response to substance, affects methylation, decreases expression, affects response to substance (+7 more)	9
stattic	increases phosphorylation, decreases expression, increases reaction, decreases phosphorylation, affects localization (+3 more)	8
Lipopolysaccharides	affects reaction, affects cotreatment, decreases reaction, increases phosphorylation, increases reaction (+2 more)	8
Cadmium Chloride	decreases reaction, increases activity, affects binding, increases reaction, decreases expression (+3 more)	8
pervanadate	decreases phosphorylation, decreases activity, decreases reaction	7
Cisplatin	decreases response to substance, increases phosphorylation, affects cotreatment, affects response to substance, decreases reaction (+3 more)	7
WP1066	affects cotreatment, decreases phosphorylation, decreases reaction, increases expression, increases phosphorylation	6
Sorafenib	decreases activity, decreases phosphorylation, increases reaction, decreases reaction, increases phosphorylation	6
Cannabidiol	decreases reaction, increases phosphorylation, affects cotreatment, decreases expression, increases expression	6
Curcumin	decreases expression, increases reaction, decreases phosphorylation, decreases reaction, increases expression (+1 more)	6
Tobacco Smoke Pollution	decreases reaction, increases phosphorylation, increases reaction, increases expression, affects expression (+1 more)	6
Raloxifene Hydrochloride	affects cotreatment, decreases reaction, increases phosphorylation, affects localization, decreases phosphorylation (+2 more)	6
pyrazolanthrone	decreases phosphorylation, decreases reaction, increases phosphorylation, increases activity	5
FLLL 32	increases phosphorylation, decreases activity, decreases phosphorylation, affects localization, decreases reaction (+1 more)	5
Bortezomib	affects cotreatment, decreases activity, decreases phosphorylation, increases reaction, increases expression (+1 more)	5
Fluorouracil	decreases phosphorylation, increases expression, affects response to substance	5
Hydrogen Peroxide	increases phosphorylation, increases ubiquitination, affects localization, decreases reaction, affects cotreatment (+2 more)	5
Nicotine	affects binding, affects cotreatment, decreases reaction, affects reaction, increases response to substance (+4 more)	5
Vanadates	increases reaction, decreases expression, decreases reaction, increases phosphorylation, affects reaction (+2 more)	5
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, affects activity, increases activity, increases reaction, increases phosphorylation (+2 more)	4

ChEMBL screening assays

1319 unique, capped per target: 1304 binding, 12 functional, 2 unclassified, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005386	Binding	Inhibition of Stat3 binding to DNA in human U266 whole cell lysate at 100 ug/ml by ELISA	Discovery of the catechol structural moiety as a Stat3 SH2 domain inhibitor by virtual screening. — Bioorg Med Chem Lett
CHEMBL1614094	Functional	PUBCHEM_BIOASSAY: Dose response counterscreen for STAT1 activators: cell-based high throughput assay to measure STAT3 activation. (Class of assay: confirmatory) [Related pubchem assays: 871, 1262, 932, 1316, 1306 ]	PubChem BioAssay data set
CHEMBL1738385	Unclassified	PUBCHEM_BIOASSAY: Late stage results from the probe development effort to identify activators of signal transducer and activator of transcription 3 (STAT3). (Class of assay: screening) [Related pubchem assays (depositor defined):AID1267, AI	PubChem BioAssay data set

Cellosaurus cell lines

30 cell lines: 13 cancer cell line, 8 transformed cell line, 6 induced pluripotent stem cell, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1149	CTB-1	Cancer cell line	Male
CVCL_1806	AMO1	Cancer cell line	Female
CVCL_A1EY	TLBR-2	Cancer cell line	Female
CVCL_A6U2	SEES3-1V human STAT3, clone1	Embryonic stem cell	Male
CVCL_A6U3	SEES3-1V human STAT3, clone2	Embryonic stem cell	Male
CVCL_A6U4	SEES3-1V human STAT3, clone3	Embryonic stem cell	Male
CVCL_A8CF	HEK-Blue IL-10	Transformed cell line	Female
CVCL_A8CG	HEK-Blue IL-22	Transformed cell line	Female
CVCL_B2HK	Abcam HeLa STAT3 KO	Cancer cell line	Female
CVCL_B8QA	Abcam HCT 116 STAT3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02624817	PHASE4	COMPLETED	Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes
NCT02624830	PHASE4	UNKNOWN	Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
NCT00466258	PHASE4	COMPLETED	LINFOTARGAM: Treatment With Chemotherapy Plus Rituximab and Highly Active Antiretroviral Therapy in Patients With Diffuse Large B Cell Lymphoma and Infection With the Human Immunodeficiency Virus (HIV)
NCT01949818	PHASE4	UNKNOWN	Treatment of Diffuse Large B Cell Lymphoma
NCT02752815	PHASE4	UNKNOWN	Reduced Chemotherapy in Low Risk DLBCL
NCT03376958	PHASE4	COMPLETED	Apatinib for Relapsed and Refractory Diffuse Large B Cell Lymphoma
NCT03513601	PHASE4	UNKNOWN	Treatment of Elderly Patients With Diffuse Large B-cell Lymphoma
NCT03579082	PHASE4	UNKNOWN	A Clinical Trial of Decitabine in Relapse and Refractory Diffuse Large B Cell Lymphoma
NCT05108805	PHASE4	COMPLETED	Chimeric Antigen Receptor (CAR) T Cell Therapy With YESCARTA in the Outpatient Setting
NCT05518383	PHASE4	RECRUITING	B-cell Mature Non-Hodgkin’s Lymphoma Treatment Protocol in Children and Adolescents 2021
NCT00033982	PHASE3	COMPLETED	Posaconazole to Treat Invasive Fungal Infections
NCT00075478	PHASE3	COMPLETED	Total-Body Irradiation With or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
NCT00355199	PHASE3	COMPLETED	Comparison of HD Chemotherapy Followed by Auto-transplant and R-CHOP in High Risk Patients With DLBCL.
NCT00400478	PHASE3	COMPLETED	A Multicentre, Randomized Phase III Study of Rituximab as Maintenance Treatment Versus Observation in Patients With Aggressive B-cell Lymphoma: NHL-13
NCT00499018	PHASE3	UNKNOWN	Dose Dense Chemotherapy + Rituximab +/-Intensified High Dose Chemoimmunotherapy With Support of Peripheral Autologous Stem Cell in Diffuse Large B-Cell Lymphoma
NCT00790036	PHASE3	COMPLETED	Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With First-line Rituximab-chemotherapy
NCT00846157	PHASE3	UNKNOWN	Biocell Natural Killer Mixture in Diffuse Large B Cell Lymphoma (DLBCL) Patients
NCT01122472	PHASE3	COMPLETED	Study of Lenalidomide Maintenance Versus Placebo in Responding Elderly Patients With DLBCL and Treated With R-CHOP
NCT01148446	PHASE3	COMPLETED	R-CHOP Versus R-mini-CEOP in Elderly Patients(>65)With DLBCL
NCT01231412	PHASE3	COMPLETED	Graft-Versus-Host Disease Prophylaxis in Treating Patients With Hematologic Malignancies Undergoing Unrelated Donor Peripheral Blood Stem Cell Transplant
NCT01285765	PHASE3	COMPLETED	Evaluate a Treatment Adapted to the PET Response Compared to a Standard Treatment, for Low Risk DLBCL CD 20+ Patients
NCT01287741	PHASE3	TERMINATED	A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA)
NCT01321541	PHASE3	COMPLETED	Comparison of Pixantrone + Rituximab With Gemcitabine + Rituximab in Patients With Aggressive B-cell Non-Hodgkin Lymphoma or Follicular Grade 3 Lymphoma Who Have Relapsed After Therapy and Are Not Eligible for Stem Cell Transplant
NCT01459887	PHASE3	COMPLETED	Study of Recombinant Human-Mouse Chimeric Anti-CD20 Monoclonal Antibody to Treat Non-hodgkin’s Lymphoma
NCT01510184	PHASE3	TERMINATED	Study of Zevalin Versus Observation in Participants at Least 60 Years Old With Newly Diagnosed Diffuse Large B-cell Lymphoma in Positron Emission Tomography (PET)-Negative Complete Remission After Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) or R-CHOP-like Therapy
NCT01804686	PHASE3	RECRUITING	A Long-term Extension Study of PCI-32765 (Ibrutinib)
NCT01852435	PHASE3	UNKNOWN	R-CEOP-90/R-CEOP-70 Versus R-CHOP-50 in the Treatment of Diffuse Large B-cell Lymphoma and Follicular Lymphoma Grade 3B
NCT02054559	PHASE3	WITHDRAWN	R-CHOP Alone vs. R-CHOP Plus Radiotherapy for Localized CD20+ DLBCL
NCT02128061	PHASE3	COMPLETED	Efficacy of Lenalidomide in Combination With Subcutaneous Rituximab + miniCHOP in DLBCL Patients of 80 y/o or+
NCT02268045	PHASE3	COMPLETED	Study of RTXM83 Plus CHOP Chemotherapy Versus a Rituximab Plus CHOP Therapy in Patients With Non Hodgkin’s Lymphoma
NCT02366663	PHASE3	TERMINATED	BEAM vs. 90-Yttrium Ibritumomab Tiuxetan (Zevalin®)/BEAM With ASCT for Relapsed DLBCL
NCT02449265	PHASE3	UNKNOWN	Efficacy of Consolidative Involved-site Radiotherapy for Patients With Limited-stage Diffuse Large B-cell Lymphoma
NCT02449278	PHASE3	UNKNOWN	The Palliative Benefit of Involved-site Radiotherapy for Patients With Advanced-stage Diffuse Large B-cell Lymphoma
NCT02531841	PHASE3	UNKNOWN	High-dose Chemotherapy and ASCT or Consolidating Conventional Chemotherapy in Primary CNS Lymphoma
NCT02617485	PHASE3	COMPLETED	MabionCD20 Compared to MabThera in Lymphoma Patients
NCT02767674	PHASE3	UNKNOWN	Trial of R-GemOx Versus R-miniCHOP Regimen in First-line Treatment of Elderly Diffuse Large B Cell Lymphoma
NCT02772822	PHASE3	UNKNOWN	A Study Comparing the Efficiency and Safety of S-CHOP(Cyclophosphamide, Hydroxydaunomycin, Oncovin, and Prednisone) Versus R-CHOP in Untreated CD20(Cluster of Differentiation Antigen 20)-Positive DLBCL Patients
NCT02777736	PHASE3	UNKNOWN	CNS Prophylaxis in Diffuse Large B-cell Lymphoma
NCT02842931	PHASE3	UNKNOWN	R-Dose-adjusted (DA) - EPOCH-21 Versus R-modified Non-Hodgkin Lymphoma (NHL)-Berlin-Frankfurt-Munster (BFM)-90 Program (mNHL-BFM-90) and Autologous Stem Cells Transplantation (Auto-SCT) in DLBCL With Poor Prognosis
NCT02951156	PHASE3	TERMINATED	Avelumab In Combination Regimens That Include An Immune Agonist, Epigenetic Modulator, CD20 Antagonist and/or Conventional Chemotherapy in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL)