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signal transducer and activator of transcription 3

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2994

Nomenclature: signal transducer and activator of transcription 3

Abbreviated Name: STAT3

Family: STAT transcription factors

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 770 17q21.2 STAT3 signal transducer and activator of transcription 3 2
Mouse - 770 11 63.82 cM Stat3 signal transducer and activator of transcription 3
Rat - 770 10q31 Stat3 signal transducer and activator of transcription 3
Gene and Protein Information Comments
Three human STAT3 isoforms have been identified: isoform 1 is the longest at 770 aa, isoforms 2 and 3 are shorter proteins (details available in Entrez Gene's 'General Protein Info' section). The mouse gene also produces multiple transcript variants and protein isoforms.
Previous and Unofficial Names Click here for help
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Database Links Click here for help
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ChEMBL Target
Ensembl Gene
Entrez Gene
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KEGG Gene
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RefSeq Nucleotide
RefSeq Protein
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Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SD-91 Small molecule or natural product Hs Binding 7.6 pKd 26
pKd 7.6 (Kd 2.8x10-8 M) [26]
Description: Determined in a biolayer interferometry (BLI) assay
SD-36 Small molecule or natural product Hs Inhibition 7.4 pKd 27
pKd 7.4 (Kd 4.4x10-8 M) [27]
Description: Binding affinity for hSTAT3, determined by fluorescence polarization assay
STAT3 inhibitor 8q Small molecule or natural product Hs Binding 7.0 pKd 14
pKd 7.0 (Kd 1.102x10-7 M) [14]
Description: Binding to full length recombinant hSTAT3 by surface plasmon resonance.
compound 6f [PMID: 35476936] Small molecule or natural product Hs Binding 6.3 pKd 10
pKd 6.3 (Kd 4.6x10-7 M) [10]
Description: Binding affinity determined in a microscale thermophoresis (MST) assay, using purified STAT3 protein (aa 127–722)
compound 8u [PMID: 31999451] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Binding 6.3 pKd 9
pKd 6.3 (Kd 5.3x10-7 M) [9]
Description: Binding dissociation constant for human STAT3 determined by SPR analysis.
SD-91 Small molecule or natural product Hs Binding 8.3 pKi 26
pKi 8.3 (Ki 5.5x10-9 M) [26]
Description: Determined in a competitive fluorescence-polarization assay
LLL12 Small molecule or natural product Hs Inhibition 7.0 pIC50 5
pIC50 7.0 (IC50 9.8x10-8 M) [5]
Description: Inhibition of IL-6 induced STAT3 transcriptional activity in human HepG2 cells, determined by luciferase reporter gene assay.
WP1066 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.8 pIC50 13
pIC50 5.8 (IC50 1.79x10-6 M) [13]
Description: Inhibition of IL-6 induced STAT3 transcriptional activity in human HEK-Blue IL-6 cells, determined in a secreted embryonic alkaline phosphatase reporter gene assay
TTI-101 Small molecule or natural product Hs Inhibition - - 11
[11]
Inhibitor Comments
A dual function TLR9 agonist-STAT3 inhibitor compound called CpG-STAT3dODN has been developed as a novel agent for B cell lymphoma immunotherapy [25]. The structure combines the TLR9 agonist agatolimod, with a high-affinity decoy oligodeoxynucleotide (dODN) STAT3 inhibitor.
Immunopharmacology Comments
STAT3 regulates the expression of a variety of genes in response to cytokines and growth factors (e.g. IFNs, EGF, IL-5, IL-6, HGF, LIF and BMP2) and plays important roles in several cellular processes, including cell growth and apoptosis. STAT3 is a crucial component of the JAK/STAT signalling pathway that is implicated in cancer and inflammation. STAT3 is frequently activated in cancers, where it downmodulates intrinsic immune surveillance of tumour cells. Phosphorylated (activated) STAT3 (pSTAT3) is a marker of poor cancer prognosis [23-24]. Inhibition of the STA3 pathway induces T cell- and NK cell-dependent growth inhibition of tumours and by this mechanism, enhances antitumour immunity [12]. Mutations in STAT3 are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome.

Selective STAT3 inhibitors are being investigated as anti-cancer immunotherapeutics and as more general immunomodulators for non-cancer inflammatory disorders. Specifically, prevention of STAT3 activation and downstream development of Th17 cell activity is viewed as a valid mechanism for the treatment of chronic inflammation.

STAT inhibition can be acheived in several ways
1) Inhibition of phosphorylation e.g. by inhibiting upstream receptor tyrosine kinase activity
2) Prevention of dimer formation: The STAT3 dimerisation inhibitor STA-21 [1,20] has completed phase 1/2 clinical trial for the treatment of psoriasis (NCT01047943) [17].
3) Prevention of pSTAT interaction with transcription factor recognition sequences: GLG-801 (a repurposed drug) inhibits binding of pSTAT3 to DNA. It has reached Phase 2 clinical development in chronic lymphocytic leukemia (CLL).4) Inhibition of STAT3 protein synthesis: AZD9150 (danvatirsen) is an antisense oligonucleotide inhibitor of STAT3 that has demonstrated clinical efficacy in solid tumours and B cell lymphoma [8,18].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
General Comments
STAT3 is constitutively activated in a large proportion of solid and hematological cancers, making it an oncology drug target [4,16]. Selective inhibition of STAT3 results in tumour cell death. OPB-111077 [21], OPB-51602 [19,22] and OPB-31121 [3,7] are lead STAT3 inhibitors that are in early stage clinical development. The chemical structures of these compounds have not been disclosed (Nov. 2022). STAT3 is also emerging as an important regulator of mitochondrial function. Inversely, STAT3 inhibitors cause mitochondrial dysfuntion, which precipitates cell death [6]. This mechanism of synthetic lethality appears to be more effective in metabolically stressed cancer cells. So both STAT3 inhibitor-driven transcriptional interference and mitochondrial disruption may both contribute to the anti-tumour cell effects of STAT3 inhibitors.

STAT3 gain-of-function somatic mutations in CD8 T cells are reported to cause autoimmune pathologies [15].

References

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1. Ahmad SF, Ansari MA, Nadeem A, Zoheir KMA, Bakheet SA, Alsaad AMS, Al-Shabanah OA, Attia SM. (2017) STA-21, a STAT-3 inhibitor, attenuates the development and progression of inflammation in collagen antibody-induced arthritis. Immunobiology, 222 (2): 206-217. [PMID:27717524]

2. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell, 77 (1): 63-71. [PMID:7512451]

3. Brambilla L, Genini D, Laurini E, Merulla J, Perez L, Fermeglia M, Carbone GM, Pricl S, Catapano CV. (2015) Hitting the right spot: Mechanism of action of OPB-31121, a novel and potent inhibitor of the Signal Transducer and Activator of Transcription 3 (STAT3). Mol Oncol, 9 (6): 1194-206. [PMID:25777967]

4. Fagard R, Metelev V, Souissi I, Baran-Marszak F. (2013) STAT3 inhibitors for cancer therapy: Have all roads been explored?. JAKSTAT, 2 (1): e22882. [PMID:24058788]

5. Gao D, Jin N, Fu Y, Zhu Y, Wang Y, Wang T, Chen Y, Zhang M, Xiao Q, Huang M et al.. (2021) Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors. Eur J Med Chem, 216: 113333. [PMID:33689932]

6. Genini D, Brambilla L, Laurini E, Merulla J, Civenni G, Pandit S, D'Antuono R, Perez L, Levy DE, Pricl S et al.. (2017) Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells. Proc Natl Acad Sci USA, 114 (25): E4924-E4933. [PMID:28584133]

7. Hayakawa F, Sugimoto K, Harada Y, Hashimoto N, Ohi N, Kurahashi S, Naoe T. (2013) A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases. Blood Cancer J, 3: e166. [PMID:24292418]

8. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, Fowler N, Zhou T, Schmidt J, Jo M et al.. (2015) AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med, 7 (314): 314ra185. [PMID:26582900]

9. Huang R, Jing X, Huang X, Pan Y, Fang Y, Liang G, Liao Z, Wang H, Chen Z, Zhang Y. (2020) Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3. J Med Chem, 63 (4): 1544-1563. [PMID:31999451]

10. Jin W, Zhang T, Zhou W, He P, Sun Y, Hu S, Chen H, Ma X, Peng Y, Yi Z et al.. (2022) Discovery of 2-Amino-3-cyanothiophene Derivatives as Potent STAT3 Inhibitors for the Treatment of Osteosarcoma Growth and Metastasis. J Med Chem, 65 (9): 6710-6728. [PMID:35476936]

11. Jung KH, Yoo W, Stevenson HL, Deshpande D, Shen H, Gagea M, Yoo SY, Wang J, Eckols TK, Bharadwaj U et al.. (2017) Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res, 23 (18): 5537-5546. [PMID:28533225]

12. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mulé J, Kerr WG et al.. (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med, 11 (12): 1314-21. [PMID:16288283]

13. Lü Z, Li X, Li K, Wang C, Du T, Huang W, Ji M, Li C, Xu F, Xu P et al.. (2021) Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors. ACS Med Chem Lett, 12 (5): 696-703. [PMID:34055214]

14. Li C, Chen C, An Q, Yang T, Sang Z, Yang Y, Ju Y, Tong A, Luo Y. (2019) A novel series of napabucasin derivatives as orally active inhibitors of signal transducer and activator of transcription 3 (STAT3). Eur J Med Chem, 162: 543-554. DOI: 10.1016/j.ejmech.2018.10.067 [PMID:30472602]

15. Masle-Farquhar E, Jackson KJL, Peters TJ, Al-Eryani G, Singh M, Payne KJ, Rao G, Avery DT, Apps G, Kingham J et al.. (2022) STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation. Immunity, Online ahead of print. DOI: 10.1016/j.immuni.2022.11.001

16. McMurray JS, Mandal PK, Liao WS, Klostergaard J, Robertson FM. (2012) The consequences of selective inhibition of signal transducer and activator of transcription 3 (STAT3) tyrosine705 phosphorylation by phosphopeptide mimetic prodrugs targeting the Src homology 2 (SH2) domain. JAKSTAT, 1 (4): 263-347. [PMID:24058783]

17. Miyoshi K, Takaishi M, Nakajima K, Ikeda M, Kanda T, Tarutani M, Iiyama T, Asao N, DiGiovanni J, Sano S. (2011) Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. J Invest Dermatol, 131 (1): 108-17. [PMID:20811392]

18. Odate S, Veschi V, Yan S, Lam N, Woessner R, Thiele CJ. (2017) Inhibition ofSTAT3with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity. Clin Cancer Res, 23 (7): 1771-1784. [PMID:27797972]

19. Ogura M, Uchida T, Terui Y, Hayakawa F, Kobayashi Y, Taniwaki M, Takamatsu Y, Naoe T, Tobinai K, Munakata W et al.. (2015) Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. Cancer Sci, 106 (7): 896-901. [PMID:25912076]

20. Park JS, Kwok SK, Lim MA, Kim EK, Ryu JG, Kim SM, Oh HJ, Ju JH, Park SH, Kim HY et al.. (2014) STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis Rheumatol, 66 (4): 918-29. [PMID:24757144]

21. Tolcher A, Flaherty K, Shapiro GI, Berlin J, Witzig T, Habermann T, Bullock A, Rock E, Elekes A, Lin C et al.. (2018) A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers. Oncologist, 23 (6): 658-e72. [PMID:29511132]

22. Wong AL, Soo RA, Tan DS, Lee SC, Lim JS, Marban PC, Kong LR, Lee YJ, Wang LZ, Thuya WL et al.. (2015) Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies. Ann Oncol, 26 (5): 998-1005. [PMID:25609248]

23. Yu H, Lee H, Herrmann A, Buettner R, Jove R. (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer, 14 (11): 736-46. [PMID:25342631]

24. Yuan J, Zhang F, Niu R. (2015) Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci Rep, 5: 17663. [PMID:26631279]

25. Zhao X, Zhang Z, Moreira D, Su YL, Won H, Adamus T, Dong Z, Liang Y, Yin HH, Swiderski P et al.. (2018) B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors. Mol Ther, 26 (3): 695-707. [PMID:29433938]

26. Zhou H, Bai L, Xu R, McEachern D, Chinnaswamy K, Li R, Wen B, Wang M, Yang CY, Meagher JL et al.. (2021) SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression. ACS Med Chem Lett, 12 (6): 996-1004. [PMID:34141084]

27. Zhou H, Bai L, Xu R, Zhao Y, Chen J, McEachern D, Chinnaswamy K, Wen B, Dai L, Kumar P et al.. (2019) Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein. J Med Chem, 62 (24): 11280-11300. [PMID:31747516]

How to cite this page

STAT transcription factors: signal transducer and activator of transcription 3. Last modified on 05/09/2023. Accessed on 23/02/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2994.