Signal Transducer and Activator of Transcription 3 (STAT3): A Promising Target for Anticancer Therapy

Abstract

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic protein whose inhibition is sought for the prevention and treatment of cancer. In this review, the validated therapeutic strategy to block aberrant activity of STAT3 in many tumor cell lines is evaluated by presenting the most promising inhibitors to date. The compounds are discussed in classes based on their different mechanisms of action, which are critically explained. In addition, their future clinical development as anticancer agents is considered. Furthermore, the efforts devoted to the comprehension of the structure-activity relationships and to the identification of the biological effects are brought to attention. The synthetic and technological approaches recently developed to overcome the difficulties in the obtainment of clinically suitable drugs are also presented.

Butein impairs the protumorigenic activity of malignant pleural mesothelioma cells

“…25 In line with this, pharmacological inhibition of NFκB or STAT3 increases the sensitivity of many solid and non-solid tumors to radio-and chemotherapy. [26][27][28] In this paper, we aim to test whether the interference with both NFκB and STAT3 activation Chronic inflammation appears to be a driving force behind cancer progression. NFκB and StAt3 activation plays a pertinent role in this process by mediating chemoresistance and the acquisition of mesenchymal features of protumorigenic cells.…”

Synthesis, structure–activity relationships and stereochemical investigations of new tricyclic pyridazinone derivatives as potential STAT3 inhibitors

“…peptides, peptidomimetics, natural compounds, small molecules and oligonucleotides, while the indirect ones can be classied as either natural or synthetic compounds. 8 A few representative STAT3 inhibitors, endowed with high activity, are reported in Chart 1. STA21 (I, the rst non-peptide inhibitor) and CDDO-Me (II, a synthetic triterpenoid derivative) are both in clinical trials;…”

“…Therefore, the design of new molecules as STAT3 inhibitors, their synthesis and the studies of their interaction with the target are very important for the development of new anticancer drugs endowed with interesting pharmacodynamic properties and reduced side effects. 8 There are two different approaches to inhibit STAT3 signaling: direct (by the interaction of the compounds with the protein) or indirect (by blocking the upstream molecules). The direct inhibitors can be divided into several classes, e.g.…”

Two serine residues of non-metastasis protein 23-H1 are critical in inhibiting signal transducer and activator of transcription 3 activity in human lung cancer cells

“…Phosphorylation of Tyr705 at the C-terminal domain of STAT3 activates STAT3. In normal cells, STAT3 is actsivated transiently, as it is tightly controlled by several negative protein modulators, including the family of suppressor of cytokine signaling proteins 1-7, Two serine residues of non-metastasis protein 23-H1 are critical in inhibiting signal transducer and activator of transcription 3 activity in human lung cancer cells the protein inhibitors of activated STATS (PIAS) and several protein tyrosine phosphatases (12)(13)(14). Therefore, the constitutive STAT3 activity in metastatic tumors may be attributed to a loss-of-function or reduction of expression of inhibitory protein during cancer progression, and tumor metastasis suppressors may also serve a role in regulating STAT3 activity.…”