signal transducer and activator of transcription 3 | STAT transcription factors | IUPHAR Guide to IMMUNOPHARMACOLOGY

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signal transducer and activator of transcription 3

  Target has curated data in GtoImmuPdb

Target id: 2994

Nomenclature: signal transducer and activator of transcription 3

Abbreviated Name: STAT3

Family: STAT transcription factors

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
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 D; 11 63.82 cM Stat3 signal transducer and activator of transcription 3
Rat - 770 3772 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
APRF
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
STAT3 inhibitor 8q Hs Inhibition 7.0 pKd 9
pKd 7.0 (Kd 1.102x10-7 M) [9]
Description: Binding to full length recombinant hSTAT3 by surface plasmon resonance.
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 [19]. 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 [17-18]. Inhibition of the STA3 pathway induces T cell- and NK cell-dependent growth inhibition of tumours and by this mechanism, enhances antitumour immunity [8]. 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 [1,14] has completed phase 1/2 clinical trial for the treatment of psoriasis (NCT01047943) [11].
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 [7,12].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 3 GO processes
GO:0006954 inflammatory response ISS
GO:0072540 T-helper 17 cell lineage commitment ISS
click arrow to show/hide IEA associations
GO:0006953 acute-phase response IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0072540 T-helper 17 cell lineage commitment ISS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0072540 T-helper 17 cell lineage commitment ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0045648 positive regulation of erythrocyte differentiation IMP
Immuno Process:  Immune system development
GO Annotations:  Associated to 2 GO processes
GO:0045648 positive regulation of erythrocyte differentiation IMP
GO:0072540 T-helper 17 cell lineage commitment ISS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 12 GO processes
GO:0019221 cytokine-mediated signaling pathway TAS
GO:0033210 leptin-mediated signaling pathway IDA
GO:0035723 interleukin-15-mediated signaling pathway TAS
GO:0038111 interleukin-7-mediated signaling pathway TAS
GO:0038113 interleukin-9-mediated signaling pathway TAS
GO:0038114 interleukin-21-mediated signaling pathway TAS
GO:0038155 interleukin-23-mediated signaling pathway TAS
GO:0045410 positive regulation of interleukin-6 biosynthetic process ISS
GO:0070102 interleukin-6-mediated signaling pathway IDA
GO:0070106 interleukin-27-mediated signaling pathway TAS
GO:0070757 interleukin-35-mediated signaling pathway TAS
GO:0071345 cellular response to cytokine stimulus TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0072540 T-helper 17 cell lineage commitment ISS
General Comments
STAT3 is constitutively activated in a large proportion of solid and hematological cancers, making it an oncology drug target [4,10]. Selective inhibition of STAT3 results in tumour cell death. OPB-111077 [15], OPB-51602 [13,16] and OPB-31121 [3,6] are lead STAT3 inhibitors that are in early stage clinical development. The chemical structures of these compounds have not yet been disclosed.

STAT3 is also emerging as an important regulator of mitochondrial function. Inversely, STAT3 inhibitors cause mitochondrial dysfuntion, which precipitates cell death [5]. 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.

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. 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. U.S.A., 114 (25): E4924-E4933. [PMID:28584133]

6. 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]

7. 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]

8. 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]

9. Li C, Chen C, An Q, Yang T, Sang Z, Yang Y, Ju Y, Tong A, Luo Y. (2018) A novel series of napabucasin derivatives as orally active inhibitors of signal transducer and activator of transcription 3 (STAT3). European Journal of Medicinal Chemistry, Articles In Press. DOI: 10.1016/j.ejmech.2018.10.067

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

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

19. 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]

How to cite this page

STAT transcription factors: signal transducer and activator of transcription 3. Last modified on 16/11/2018. Accessed on 17/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2994.