Pharmacological Inhibition of TAK1 as a Therapeutic Target to Reduce Inflammation and Pain

Abstract

Chronic pain is a prevalent health concern, affecting up to 100 million people in the US alone, yet treatment options remain limited. The origins of pain have been tightly linked to inflammation and in specific tumor necrosis factor (TNF) a pro-inflammatory cytokine, has been identified as a key driver of pain and inflammation. TNF can bind to its TNFR1 receptor located on the terminals of primary afferent nociceptors to directly increase their activity. In addition, TNF can stimulate pro-inflammatory cytokine production and immune cell activation. Patients with chronic pain exhibit increased levels of TNF, with higher levels in those with greater pain. TNF antibodies (eg, Remicade, Humira and Cimzia) are currently available for the treatment of inflammatory pain conditions such as rheumatoid arthritis. However, 40% of patients fail to respond to TNF antibodies, leading for the need to develop novel small molecule TNF inhibitors. TGFβ-activated kinase (TAK1) inhibition has been previously shown to potently reduce TNF signaling. Takinib, a potent inhibitor of TAK1 represents a novel method of regulating TNF production and pro-inflammatory signaling. Here, I show that TAK1 inhibition prevents inflammatory, neuropathic and functional pain by modulating immune responses and nociceptor activity. Overall, our findings support the therapeutic potential of a TAK1 inhibitor as a novel therapeutic to reduce inflammation and chronic pain.