https://orcid.org/0000-0002-8209-5263
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ABSTRACT
Introduction
STAT3 is a critical transcription factor that transmits signals from the cell surface to the nucleus, thus influencing the transcriptional regulation of some oncogenes. The inhibition of the activation of STAT3 is considered a promising strategy for cancer therapy. Numerous STAT3 inhibitors bearing different scaffolds have been reported to date, with a few of them having been considered in clinical trials.
Areas covered
This review summarizes the advances on STAT3 inhibitors with different structural skeletons, focusing on the structure-activity relationships in the related patent literature published from 2014 to date.
Expert opinion
Since the X-ray crystal structure of STAT3β homo dimer bound to DNA was solved in 1998, the development of STAT3 inhibitors has gone through a boom in recent years. However, none of them have been approved for marketing, probably due to the complex biological functions of the STAT3 signaling pathway, including its character and the poor drug-like physicochemical properties of its inhibitors. Nonetheless, targeting STAT3 continues to be an exciting field for the development of anti-tumor agents along with the emergence of new STAT3 inhibitors with unique mechanisms of action.
Article highlights
Targeting STAT3 is still an exciting field in the development of anti-tumor agents along with the emergence of new STAT3 inhibitors with unique mechanisms of action.
STAT3 inhibitors with different structural scaffolds described from 2014 to date were summarized, and their structure-activity relationships and biological activities were also discussed.
Patents related to dual STAT3 inhibitors and STAT3 degraders were discussed and summarized.
The development of potent allosteric inhibitors of STAT3 may bring new hope for the treatment of diseases.
List of abbreviations
| STATs | = | Signal Transducer and Activator of Transcriptions |
| IFN | = | Interferon |
| IL-12 | = | Interleukin-12 |
| NTD | = | N-terminal domain |
| CCD | = | Coiled-coil domain |
| DBD | = | DNA-binding domain |
| LD | = | Linker domain |
| SH2 | = | Src homology 2 |
| TAD | = | Transactivation domain |
| GPCRs | = | G‑protein‑coupled receptors |
| TLRs | = | Toll‑like receptors |
| PIAS | = | Protein inhibitor of activated STAT |
| SOCS | = | Suppressor of cytokine signaling |
| ETC | = | Electron transport chain |
| BTP | = | benzo[b]thiophene 1,1-dioxide |
| PROTACs | = | Proteolysis targeting chimeras |
| FBDD | = | Fragment-based drug design |
| AMLSD | = | Advanced multiple ligand simultaneous docking |
| MST | = | Microscale thermophoresis |
| BLI | = | Biolayer interferometry |
| EAE | = | Experimental autoimmune encephalomyelitis |
| MS | = | Multiple Sclerosis |
| CBT | = | 2-carbonylbenzo[b]thiophene 1,1-dioxide |
| TNBC | = | Triple negative breast cancer |
| HNSCC | = | Head and neck squamous cell carcinoma |
| NACLC | = | Non-small cell lung cancer cells |
| ELISA | = | Enzyme linked immunosorbent assay |
| AML | = | Acute myelogenous leukemia |
| EMSA | = | Electrophoretic mobility shift assay |
| NMR | = | Nuclear magnetic resonance |
| SPR | = | Surface plasmon resonance |
| GST | = | Glutathione-S-transferase |
| TCM | = | Traditional Chinese medicine |
| MuRF1 | = | Muscle ring-finger containing protein-1 |
| MAFbx | = | Muscle atrophy Fbox protein |
| IDO1 | = | Indoleamine-2,3-dioxygenase 1 |
| POI | = | Protein of interest |
| UPS | = | ubiquitin-proteasome system |
Declaration of interests
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.