This is achieved using either non specific inhibitors such as cur cumin, which also inhibits other transcription factors, or inhibitors specifically designed to inhibit STAT3 through non covalent binding to the SH2 domain, such as Stattic or STA 21. Interestingly, these com pounds have little effect in cells in which STAT3 is not activated, pointing to STAT3 as a highly Inhibitors,Modulators,Libraries valid target to focus on for the design of anti cancer compounds. How ever, such compounds are still poorly developed. TFs activate transcription of Inhibitors,Modulators,Libraries their target genes by binding to distinct short DNA consensus motifs. Decoy oligonucleotides containing these consensus motifs can bind the DNA binding domains of the Carfilzomib TFs and block their activity.
dODNs and hairpin dODNs have been shown to induce the death of cells in which STAT3 is activated, suggesting that the DBD is another potential target for specific inhibitory compounds. Similarly to double stranded oli gonucleotides that are used to detect active dimers in electrophoretic Inhibitors,Modulators,Libraries migration shift assays, STAT3 hpdODNs interact with activated, dimeric STAT3. This interaction impairs the binding of the dimer to importins, resulting in the sequestration of STAT3 in the cytoplasm. Yet, because of the high degree of similarity between STAT3 and STAT1 consensus DNA binding sites, STAT1 competes with activated STAT3 for dODN binding in interferon g treated cells, thereby preventing inhibition of active STAT3. Under such conditions the dODN loses its ability to block cell proliferation.
In addition, since STAT1 plays a key role in cell death processes, Inhibitors,Modulators,Libraries including caspases e pression and cooperation with p53 function, its inhibition by the dODN prevents cell death. Finally, IFNg being a cell death inducer in several cell types, it is important to design reagents that do not interfere with STAT1, one of its key effectors. Thus, in order to elaborate target specific anti cancer compounds, the specificity of hpdODNs to STAT3 needs to be enhanced. It should be noted, however, that in certain cellular conte ts STAT1 has been found to be a tumor promoter. The difficulty in designing dODNs recognized by STAT3 but not STAT1 lies in the striking similarity of the consensus DNA sequences of the two TFs, in spite of their different cellular functions.
Nevertheless, early stu dies on STAT3 STAT1 discriminating DNA motifs estab lished some sequence preferences that differentiate these TFs, suggesting possibilities for designing STAT3 STAT1 discriminating dODNs. The notion that discrete nucleotide modifications in target DNA sequences might alter their recognition by closely related TFs is supported by the observation that a single nucleotide change in the B consensus motif modified NF B subunit specificity. Furthermore, DNA recognition by proteins relies in part on DNA shape, known to deviate from the ideal B conformation.