TAK-242

Background

TAK-242 is a small-molecule that specifically inhibits Toll-like receptor 4 signaling through binding to the intracellular domain of TLR4 at Cys747 (1). TLR4 triggers activation of the NF-κB, IRF-3, and MAPK pathways, leading to production of inflammatory cytokines. TAK-242 inhibits binding between TLR4 and adaptor molecules, including Toll/interleukin-1 (IL-1) receptor domain-containing adaptor protein (TIRAP), which blocks activation of NF-κB and other downstream signaling events (2). In LPS-stimulated mouse macrophages, TAK-242 suppressed the production of NO and the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (3). In a study of LPS-induced myotube atrophy, TAK-242 provides a protective effect by inhibiting TLR4 and suppressing TNF-α- and IL-6-mediated inflammatory responses. Similar results were seen in a mouse model of endotoxemia, with TAK-242 inhibiting activation of inflammatory and proteolytic pathways and reversing the muscle wasting impact induced by LPS treatment (4).