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 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

   GtoImmuPdb view: ON :     signal transducer and activator of transcription 3 has curated data in GtoImmuPdb

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
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 [15]. 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. Mutations in STAT3 are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. STAT transcription factors are being investigated as drug targets for the development of novel therapeutics, not only for cancer, but also for immunomodulatory potential. 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 [1,12] has completed phase 1/2 clinical trial for the treatment of psoriasis (NCT01047943) [9].
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 is an antisense oligonucleotide inhibitor of STAT3 that has demonstrated clinical efficacy in solid tumours and B cell lymphoma [7,10].
General Comments
STAT3 is constitutively activated in a large proportion of solid and hematological cancers, making it an oncology drug target [4,8]. Selective inhibition of STAT3 results in tumour cell death. OPB-111077 [13], OPB-51602 [11,14] 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. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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 13/03/2018. Accessed on 15/12/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2994.