Takinib, a selective TAK1 inhibiting drug, has been shown to broaden the therapeutic efficacy of TNF-alpha (Tumor necrosis factor-alpha) inhibition for treating cancer and autoimmune diseases.
TAK1 (also known as MAP3K7 or mitogen-activated protein kinase kinase kinase 7) is a key mediator between survival and cell death in TNF-alpha-mediated signaling. TNF-alpha is a cytokine that has a wide variety of functions. It can cause cytolysis of certain tumor cell lines and is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion. It can stimulate cell proliferation and induce cell differentiation under certain conditions.
Investigators at Duke University (Durham, NC, USA) recently described the compound Takinib, a potent and selective TAK1 inhibitor that induced apoptosis following TNF-alpha stimulation in cell models of rheumatoid arthritis and metastatic breast cancer.
The investigators used X-ray crystallography to demonstrate that Takinib was an inhibitor of autophosphorylated and non-phosphorylated TAK1 that bound within the ATP-binding pocket and inhibited TAK1 by slowing down the rate-limiting step of TAK1 activation.
Overall, the investigators saw Takinib as an attractive starting point for the development of inhibitors that sensitize cells to TNF-alpha-induced cell death, with general implications for cancer and autoimmune disease treatment.
“The delicate balance between survival and death is often disrupted in disease, and this molecule is able to target the process,” said senior author Dr. Timothy Haystead, professor of pharmacology and cancer biology at Duke University. “This compound could potentially enhance the positive parts of TNF-alpha by only targeting tumor cells or inflammatory cells.”