A major problem, which influences the development of specific inhibitors of p38, dosedependent toxicity is t. Structurally different compounds caused Hepatotoxizit t, indicating that this side effect is the objective can Base. In another phase II study, the p38 inhibitor VX-702 QT Verl Caused EXTENSIONS. Based on the number of compounds that have been tested, it is clear that targeting p38 NVP-BKM120 is not as easy as we had hoped. Several m Possible solutions L Were emerged in recent years, including normal kinases downstream Rts or upstream Rts involved in p38 biology. These strategies can k Modulate a certain advantage p38 signaling improve while maintaining other essential functions and the side effect profile. JNK and ERK inhibitors in rheumatic diseases are less advanced. JNK embroidered the activator protein 1 dep-Dependent genes, including normal matrix metalloproteinases and animal studies with inhibitors of JNK showed protection against Knochenl Emissions.
However, inhibitors of JNK have been developed not available in rheumatic diseases and may further questions about the efficacy and selectivity T have. MKK7, an upstream Rts activator of JNK kinase for the prim Re activation of JNK after cytokine stimulation of FLS is required. Since the events ZSTK474 of cellular Ren stress deal k Can MKK7 and MKK4 to stimulate JNK use, targeting MKK7 s failed Rs be broad acting JNK inhibitors. Targeting of the transcription complex AP-1 downstream Rts, as with decoy oligonucleotide is an alternative to focus on JNK. AP-1 is of dimers, the members of the Jun, Fos, and activating transcription factor family of proteins go Ren assembled there embroidered slowly together a variety of genes, including normal MMPs and inflammatory cytokines. c-Fos deficient M missing nozzles osteoclasts and protected against bone erosions, but not inflammation in TNF transgenic model.
A small molecule anti-AP-1 activity of t has to be effective in the CIA. Interestingly, this compound is also reduced IL-1 and the joint inflammation, an indication that it has a significant effect on the AP-1 transcription entered Born. No significant toxicity t In animal studies have been reported, but a sorgf require insurance valid test in human trials. ERK plays an r Important role in the regulation of cell growth and k Nnte Be an important therapeutic advance in the treatment of cancer. ERK inhibitors are also effective in some animal models of arthritis. The small molecule inhibitor of MEK1 / 2, ERK kinase upstream Rts inhibits ex vivo production of IL-1, TNF, IL-6, and human whole blood after administration to healthy volunteers regulated.
Similar to other MAP pathway inhibitors but have toxicity Th due to the r Came the omnipresent Rtige ERK. It may be desirable to modulate, pleased t that be to block these canals le through a strict selection pharmacokinetic profiles and dosing. Tyrosine kinase tyrosine kinases are divided into two groups. Cytoplasmic kinases transduce signals to a surface Chenrezeptor separate, w During receptor intrinsic activity t Of tyrosine phosphorylation have. Four Janus kinases are cytoplasmic tyrosine kinases that In at least six different combinations of cytokines and signaling integrated pair nearly 40 different growth factors.