# Carbazole Derivatives as STAT Inhibitors: An Overview
## 3 STATs Inhibitors  
### Peptides and Small Molecules as STATs Inhibitors  
Activation of STAT1, STAT3, and STAT5 is highly frequent in almost all tumors studied, with a higher incidence of abnormal STAT3 activation [66]. Starting from the breakthrough of the first peptide inhibitor of a STAT protein, diverse strategies to counteract against STAT signaling have been pursued. An example is provided by small-molecule dimerization disruptors (SMDDs) or phospho-peptiddomimetic inhibitors (PPMIs) targeting the phospho-Tyr-SH2 domain interaction at the interface of dimers of STAT proteins. The main consequence consists of the disruption of STAT-STAT dimers. STAT-SMDD or STAT-PPMI forms heterocomplexes, suppressing STAT signaling and function. On the other hand, the bond between growth factors and cytokines and their receptors on the cell surface activates STAT tyrosine phosphorylation. Tyrosine kinases responsible for STAT phosphorylation are the targets of small-molecule tyrosine kinase inhibitors. These modulators can prevent the induction of STAT phosphorylation and signaling. They act by impeding STAT dimerization using peptides or peptidomimetics identified through different processes as structure-based design, small molecules identified by molecular modeling, virtual or library screening, or natural products [66]. Other methods, comprise oligodeoxynucleotide (ODN) decoys (peculiar STAT DNA-binding domain inhibitors) and antisense oligonucleotides (ASOs) that interfere with STAT mRNA. Studies on the molecular basis of oncogenesis, regarding oncoproteins like v-Src, report alterations in intracellular signaling proteins involved in several malignancies. The discovery that STAT3 is constitutively activated in v-Src transformation indicated the possible central role of STATs in oncogenesis [67; 68]. Additionally, other transforming tyrosine kinases such as v-Eyk [69], v-Ros [70], v-Fps [71], Etk/ BMX [72], and Lck [73], activate STAT3 in the oncogenic process. Constitutive STAT3 activation is also connected with the transformation caused by tumor viruses, among which are HTLV-1 [74], polyomavirus middle T antigen [75], EBV [76], and herpesvirus suimiri [73], that directly or indirectly activate JAKs or Src family tyrosine kinases. For the reasons explained above, different therapeutic agents, targeting aberrantly active STAT3, could affects several human cancers making STAT3 the target in many drug discovery research efforts. STAT3 drug discovery research concentrated on targeting the pTyr-SH2 domain interaction [77; 78] due to its relevance in promoting STAT3 dimerization and function. A semirational, structure-based design study determined the first SH2 domain-binding peptides and peptidomimetics that break up the STAT3 pTyr-SH2 domain interactions and STAT3-STAT3 dimerization [78; 79]. The native parent pTyr peptide, PY*LKTK (where Y* stands for pTyr) and its modified forms prevented the DNA-binding and transcriptional activities of STAT3 at high doses [79]. Peptiddomimetic and non-peptide analogues, such as ISS-610 and S3I-M2001, counteracted STAT3 activity in vitro and accommodated aberrantly active STAT3 [78; 79]. In particular, S31-M2001 constrained the progression of human breast tumor xenografts, while ISS-610 blocked cell growth and triggered apoptosis in vitro [66]. Moreover, phosphopeptide binding sequences with the primary structure pTyr-Xxx-Xxx-Gln (where Xxx represents any amino acid) impeded STAT3 activation. They derived from leukemia inhibitory factor (LIF), IL-10 receptor, epidermal growth factor receptor (EGFR), granulocyte colony-stimulating factor (GCSF) receptor, or glycoprotein 130 (gp130) [80; 81]. In this research, the peptidomimetic Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH\({}_{2}\) inhibited STAT3 activity (IC\({}_{50}\) values of 150 n\(\upmu\)M) [81; 82]. Furthermore, a 28-mer native peptide identified as SPI, obtained from the STAT3 SH2 domain, hampered the STAT3 pTyr-SH2 domain interaction and signaling.