Furthermore, recent proof suggests that drugs now applied as anticancer agents may possibly perform no less than in element through the depletion of STAT1. By way of example, the purine analog fludarabine is surely an powerful agent in CLL. Though fludarabine was hy pothesized to act via incorporation into DNA, rather couple of CLL cells are traversing the cell cycle at any provided time, making such a mechanism unlikely. Given that inappropriate STAT serine phosphorylation is actually a hallmark of CLL, it was hypothesized that fludarabine may do the job by interfering with STAT signaling. The truth is, fludarabine leads to a pronounced and certain reduction of STATI. This may well underlie both the antineoplastic actions of fludarabine as well as the immunosuppression that accompanies using this drug, which is just like that seen in STAT1 deficient animals. These discover ings strengthen the hypothesis that STAT inhibition is often a probably very important target in can cer therapy. Targeting STAT DNA Binding Even if STATs turned out to be phosphorylated within a cell, they cannot exert their biological result till they bind to specific DNA sequences during the professional moters of target genes.
Consequently, inhibiting the abil ity of an activated STAT dimer to bind to its target DNA is surely an helpful tactic to inhibit STAT mediated transcriptional activation. Sev eral approaches might be envisioned. The very first in volves inhibiting the translocation kinase inhibitor Perifosine of activated STATs in the cytoplasm, where they’re phos phorylated, towards the nucleus, the place they exert their results. Having said that, the mechanisms that reg ulate the course of action of nuclear localization are poorly understood, and thus its inhibition could be a distant objective. Alot more virtually, it can be conceiv ready the potential of an activated STAT to bind to a target sequence in the promoter region might be inhibited. One particular strategy entails the produce ment of little molecule inhibitors that could in teract with all the DNA binding web sites of activated STATs, therefore stopping the binding to a pro moter sequence.
A 2nd strategy, which may very well be designed alot more without difficulty, requires the introduction to the cell of short stretches of double stranded DNA which mimics the target STAT binding sequence. These decoy oligonu cleotides would be present in fantastic molar extra in excess of the endogenous sequences within promoter regions. When a STAT turns into activated, it will bind to the decoy oligonucleotide, pre cluding its interaction with the target gene professional moters. Such a technique could diminish the capacity DCC-2036 of STATs to activate genes crucial for neoplastic cell development, and might be particularly practical in combination with inhibitors of STAT phosphor ylation. Dominant Inhibitory STATs STATs may also be inhibited by dominant inhib itory kinds. This kind of STATs, which lack a DNA bind ing domain or perhaps a transactivation domain, can nevertheless from dimers with endogenous STATs.