Small Molecule Inhibition of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4)

In recent years, interleukin-1 receptor-associated kinase 4, IRAK4, has become an attractive target for many medicinal chemistry programmes. Target inhibition is of potential therapeutic value in areas including autoimmune disorders, cancer, inflammatory diseases, and possibly neurodegenerative diseases. Results from high-throughput screening efforts have led, in conjunction with structure-based drug design, to the identification of highly potent and selective small molecule IRAK4 inhibitors from many diverse chemical series. In vitro and in vivo studies with entities from distinct structural classes have helped elucidate the downstream pharmacological responses associated with IRAK4 inhibition as a proof of concept in disease models, leading to the recent initiation of human clinical trials. Within this review, we will highlight the considerable effort by numerous groups dedicated to the development of small molecule IRAK4 inhibitors for the treatment of human disease.