# Carbazole Derivatives as STAT Inhibitors: An Overview
## 2 STAT Proteins: Novel Molecular Targets for Cancer Drug Discovery  
Signal transducers and activators of transcription (STATs) constitute a group of cytoplasmic proteins that function as signal messengers and transcription factors engaged in critical cellular events with the use of multiple cytokines and growth factors. Since tyrosine has been phosphorylated, two STAT monomers develop dimers via mutual phosphotyrosine-SH2 interactions, migrate to the nucleus, and bind to STAT-specific DNA-response elements of target genes that cause gene transcription. Concerning the biological functions of STATs, they contribute to cell differentiation, proliferation, development, apoptosis, and inflammation [33; 34]. Indeed, STATs are typical transcription factors. They directly engage DNA regulatory elements (DREs) and thereby control the transcription of associated genes, linked to specific functions [35]. Up to now, seven STAT family members have been detected in mammals, designated as STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. The existing connection between the immune system cells and the JAK-STAT pathway has long been studied. Concerning the gain- or loss-of-functions mutation in genes encoding for JAK-STATs, immunodeficiency and susceptibility to infections are the most widespread phenotypes, demonstrating the crucial role of Jak-STAT signaling in the development and function of immune cells. STAT1 signaling, for example, suppresses type 17 immunity, which makes mice more susceptible both to bacterial and viral infections [36]. Indeed, it is involved in povaviruses, which encode interferon-receptor homologs; vaccinia viruses, which encode phosphatases; and Epstein-Barr viruses, encoding a protein that subverts multiple components of the interferon-STAT1 [35]. Additionally, STAT1 exerts a multidirectional antitumor effect. It blocks the cell cycle progression and angiogenesis and induces proapoptotic genes. Moreover, STAT1 signaling governs T helper type 1 (TH1) cell-specific cytokine production that changes both immune functions and inflammatory  
Figure 4: Structures of 3-methylcarbazole (**9**) and 2-methylcarbazole (**10**). responses by modifying the ratio between TH1 and TH2 cells. Furthermore, STAT1 has tumor-suppressing properties like TP53 and could be an antagonist for STAT3 and STAT5 activation. Besides, many studies corroborate the relationship between STAT1 downstream of interferons and NF-\(\kappa\)B downstream of Toll-like receptors or the cytokine TNF, the two pathways can promote or 'prime' each other [35; 37]. STAT2 signaling, instead, is important for its antiviral effects [38]. Further evidence indicates that altered STAT2 signaling may play a role in carcinogenesis by upregulating interleukin-6 (IL-6) production, which activates STAT3 [38]. Previous works demonstrated that in vitro cultured STAT3-deficient T cells did not react to IL-6 stimulation and could not be saved by IL-6 from apoptosis, demonstrating that STAT3's role is crucial for IL-6-mediated anti-apoptotic responses. Further, STAT3 altered functions in keratinocyte physiology could induce skin carcinogenesis. Moreover, constitutively active STAT3 has been identified in several malignancies, among which are breast, melanoma, prostate, head, and neck squamous cell carcinoma (HNSCC), multiple myeloma, pancreatic, ovarian, and brain tumors [39; 40; 41; 42; 43]. Aberrant STAT3 signaling stimulates tumorigenesis in part by modifying the expression of genes that rule the tumor growth processes. Examples are offered by genes encoding for p21 WAF1/CIP2, cyclin D1, MYC, BCL-XL, BCL-2, vascular endothelial growth factor (VEGF), matrix metalloproteinase 1 (MMP1), MMP7 and MMP9, and survival [44]. A recent study demonstrated that unphosphorylated STAT3 possesses the function of promoting heterochromatin formation in lung cancer cells, suppressing cell proliferation in vitro, and suppressing tumor growth in mouse xenografts [45].