# Carbazole Derivatives as STAT Inhibitors: An Overview
## 2 STAT Proteins: Novel Molecular Targets for Cancer Drug Discovery
Furthermore, transforming growth factor-\(\alpha\) (TGF-\(\alpha\))-mediated epidermal growth factor receptor (EGFR) signaling plays a vital role in the activation of STAT3 in some head and neck cancer cell lines [46]. In addition, STAT3 mutations were identified in multiple peripheral T-cell lymphomas (PTCL), along with high pY-STAT3 expression, particularly in angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) patient samples, two different PTCL cancer types [47]. By modulating the genetic and pharmacological profile of persistently active STAT3, it is possible to hamper the tumor progression _in vivo_. STAT4 is also essential for IL-12 function, which governs the differentiation of TH1 cells and their inflammatory responses [48]. Therefore, STAT4 signaling is related to autoimmune diseases [49]. STAT5 is present in two isoforms, STAT5a and STAT5b [50]. Normal STAT5 signaling is crucial in mammary gland development, milk production, and hematopoiesis [51]. Constitutive STAT5 triggering is also involved in the development of HNSCC, chronic myelogenous leukemia (CML) [52], and breast, prostate, and uterine cancers [53]. In particular, the effects could be related to the aberrant STAT5 activation by BCR-ABL in CML43 protein. Indeed, it is extensively accepted that STAT5 and STAT3 have in common equal functions in promoting cancer, inducing the expression of pro-proliferative and anti-apoptotic genes [54; 55]. Mice lacking both STAT5A and STAT5B showed a large variety of immunological defects and died soon after birth. In addition, the lineage-restricted deletion of STAT5 has been key in defining its in vivo functions, including the role in CD4\({}^{+}\) T cell differentiation, NK-cell-mediated immunosurveillance, CD8\({}^{+}\) T cell memory187, DC-lineage specification and DC-driven type 2 inflammation. [35] In addition, STAT5A and B are implicated in chronic myeloid leukemia. In fact, the transfection of K-562 leukemia cells either with anti-STAT5A or anti-STAT5B, led to a greatly increased apoptosis rate [56]. IL-4 and IL-13 trigger STAT6 signaling that sustains immune function and regulates the equilibrium between inflammatory and allergic immune responses [57; 58]. STAT6 signaling also supports luminal mammary epithelium progression and is involved in the pathology of lung and airway diseases, [59; 60; 61]. A recent study assessed that E2F1 is essential for maintaining the level of signal transducer and activator of STAT6 in HCT116 colorectal cancer cells. Mechanistically, E2F1 induced specificity protein 3 (SP3) directly binds to the promoter of the STAT6 gene and activates its transcription in CRC cells. As a result, it was demonstrated that the E2F1/SP3/STAT6 axis is required for the IL-4-induced epithelial-mesenchymal transition of colorectal cancer cells [62]. Linked to STAT proteins are Janus kinases (JAK1, JAK2, JAK3, and TYK2) enzymes, structurally related to each other, with tyrosine kinase activity assisting in the passage of signals from the cell surface to the inside. The JAKs pathways are implicated in the onset of many inflammatory and autoimmune pathologies, among which are rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. The main reason is due to the use of the JAK-STAT3 pathway by a substantial amount of cytokines and hormones for intracellular signaling. Indeed, in psoriasis, diverse cytokines implicate the JAK-STAT pathway, such as type I and II IFN, IL-12, IL-22, IL-23, and IL-13. In particular, JAK activation starts, at first, upon ligand-mediated receptor multimerization because two JAKs are brought into proximity, allowing trans-phosphorylation. The subsequent step includes the phosphorylation of a conserved tyrosine residue near the C-terminus of STATs by activated JAKs [63]. Concerning the JAKs family, JAK1, JAK2, and TYK2 expression can be detected throughout the whole body. On the contrary, JAK3 has been specifically identified in the hematopoietic cells.