# Carbazole Derivatives as STAT Inhibitors: An Overview
## 3 STATs Inhibitors
### Peptides and Small Molecules as STATs Inhibitors
It suppressed cell viability and caused programmed cell death of human breast, pancreatic, prostate, and non-small cell lung cancer (NSCLC) cells in vitro [83]. In silico studies of chemical libraries detected several small-molecule inhibitors of STAT3 activity. The main mechanism regards the disruption of STAT3-STAT3 dimerization. STA-21 (or NSC628869) was recognized from the screening of the National Cancer Institute (NCI) chemical library as an inhibitor of STAT3 dimerization, DNA-binding activity, and transcriptional function in breast cancer cells at 20 \(\upmu\)M [84]. Its structural analogue, LLL-3 (with enhanced membrane permeability), reduced cell viability in vitro and intracranial tumor size in vivo in glioblastoma animal models [85]. Moreover, a catechol (1,2-dihydroxybenzene) compound was detected from [PERSON]'s proprietary small-molecule collection as a STAT3 SH2 domain inhibitor, active at 106 \(\upmu\)M against a multiple myeloma cell line [86]. In addition, S3I-201 (or NSC74859) as a STAT3-STAT3 dimerization disruptor active at 60-110 \(\upmu\)M [87] also emerged from the NCI chemical library. S3I-201 hampered STAT3 DNA-binding and transcriptional activities, inhibited cellular growths, and promoted the apoptotic process of tumoral cells harboring constitutively active STAT3, and suppressed the growth of human breast cancer xenografts [87]. Several of its derivatives, such as S3I-201.1066, BP-1-102, and S3I-1757, exhibited a better efficacy, with IC\({}_{50}\) values of 35 \(\upmu\)M (S3I-201.1066), 6.8 \(\upmu\)M (BP-1-102), and 13.5 \(\upmu\)M (S3I-1757), and suppressed cell growth, malignant transformation, survival, migration and invasiveness in vitro of malignant cells harboring aberrantly active STAT3. Moreover, Cpd30 (4-(5-(3-ethyl-4-oxo-2-thioxo-1,3-thiazol-5-ylidene)methyl)-2-furyl)benzoic acid) (Figure 5) moderately blocked STAT3, prevented STAT3 nuclear translocation upon IL-6 stimulation, and triggered apoptosis in breast cancer cells harboring constitutively active STAT3 [54]. Its analogue, Cpd188 (4-((3-(carboxymethyl)thio)-4-hydroxy-1-naphthyl)amino)sulphonylbenzoic acid) (Figure 5), combined with docetaxel, lowered tumor growth in chemotherapy-resistant human breast cancer xenograft models. From another virtual screening of small molecules emerged Stattic, a non-peptide small molecule able to target the STAT3 SH2 domain and inhibit STAT3 signaling at 10 \(\upmu\)M [88]. It triggered apoptosis of STAT3-dependent breast cancer and neck squamous cell carcinoma HNSCC cells and arrested growth of orthotopic HNSCC tumor xenografts [88]. STX-0119, STAT3 SH2 domain antagonist generated antitumor effects both in vitro and in vivo in a human lymphoma model, probably by disrupting STAT3-STAT3 dimerization, with a modest activity on STAT3 phosphorylation [89]. Fragments of STX-0119 and static were chemically combined to create HJC0123 (Figure 5) [90], which impeded STAT3 phosphorylation and transcriptional activity in breast cancer cells and possessed antiproliferative effects towards breast and pancreatic cancer cells in vitro (IC\({}_{50}\) values of 0.1-1.25 \(\upmu\)M). The oral administration of HJC0123 blocked the growth of human breast cancer xenografts [90]. Furthermore, OBP-31121 inhibited STAT1, STAT3, and STAT5 phosphorylation. OBP-31121 reduced cell proliferation and triggered apoptosis in vitro whereas it prevented tumor growth in vivo in gastric cancer models, and it further sensitized gastric cancer cells to cisplatin and 5-fluorouracilacil [91].