Resumen de Chapter Nine - Advances in the Discovery of Small-Molecule IRAK4 Inhibitors
John Hynes Jr., Satheesh K. Nair
Abstract Therapeutic targeting of innate immune system pathways in chronic inflammatory diseases, such as rheumatoid arthritis and lupus, may provide additional therapies for patients afflicted with these conditions. Interleukin-1 receptor-associated kinase 4 (IRAK4), a serine/threonine kinase, is a key molecule downstream of the innate signaling toll-like receptors (TLRs). The TLRs are activated by endogenous pathogens associated with necrotic cell death and tissue damage, hallmarks of chronic inflammation. Additionally, IRAK4 is downstream of the key proinflammatory signaling IL-1 family of receptors. Several biologic IL-1-targeting therapies have been approved, and an IRAK4 inhibitor would be an attractive alternative for targeting this pathway. Finally, aberrant signaling of the IRAK4 pathway due to activating mutations in the MyD88 adaptor protein has been implicated in certain cancers. Accordingly, IRAK4 inhibitors may provide additional options for the treatment of chronic inflammatory diseases and cancers. A summary of the recent structural classes of IRAK4 inhibitors is provided.
