Takinib, an inhibitor of the protein TAK1, was found to interrupt the inflammatory response central to a variety of autoimmune disorders, such as Crohn’s disease, research shows.
The study, “Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease,” was published in the journal Cell Chemical Biology.
Takinib is a drug-like molecule that acts to increase cell death and decrease inflammation. TAK1 is part of the TNF-α inflammatory pathway.
TNF-α is the major cause of inflammation in autoimmune diseases as it promotes pathways that lead to cell survival and inflammation. When stimulated by TNF-α, TAK1 becomes activated and causes inflammation as well as cell survival. When TAK1 is not activated, TNF-α stimulation causes the cell to undergo cell death (apoptosis). Therefore, the presence of TAK1 determines whether a cell survives or dies when it is stimulated by TNF-α.
Patients with autoimmune diseases are generally treated with anti-TNF-α antibodies to control the disease and decrease inflammation. However, during chronic treatment, patients often become resistant to these antibodies and other pharmaceutical drugs that inhibit inflammation.
Researchers at Duke University developed the molecule Takinib, which pushes the cell toward apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer.
“The delicate balance between survival and death is often disrupted in disease, and this molecule is able to target the process,” Timothy Haystead, PhD, a professor in the Department of Pharmacology and Cancer Biology at Duke, said in a press release. “This compound could potentially enhance the positive parts of TNF-alpha by only targeting tumor cells or inflammatory cells.”
Interestingly, Takinib appears to be effective in small volumes, which leads to less toxicity. This is particularly encouraging as some of the other drugs that target inflammatory pathways are also very toxic to cells and tissue.
“Takinib is unique for its ability to selectively target a pathway, since many inhibitors shut everything down,” said Emily Derbyshire, PhD, assistant professor in Duke’s Department of Chemistry. “It appears to have a more surgical ability to inhibit this pathway.”
Additional studies are being conducted to test Takinib in animals to determine its effect on rheumatoid arthritis and whether it could be used in the context of other diseases such as malaria. The authors of the study note that Takinib is an attractive starting point for the development of inhibitors that make cells sensitive to TNF-α induced death.
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