Emerging trends in IRAK-4 kinase research.

The IRAK-4 kinase lies at a critical signaling node that drives cancer cell survival through multiple mechanisms, activation, and translocation of NF-κB mediated inflammatory responses and innate immune signaling through regulation of interferon-α/β receptor (IFNα/β). Inhibition, of IRAK-4, has consequently drawn a lot of attention in recent years to address indications ranging from oncology to autoimmune disorders to neurodegeneration, etc. However, the key stumbling block in targeting IRAK-4 is that despite the inhibition of the kinase activity using an inhibitor the target remains effective, reducing the potential of an inhibitor. This is due to the "scaffolding effect" because of which although regulation of downstream processes by IRAK-4 has been primarily linked with kinase function; however, still, various reports have suggested that IRAK-4 has a non-kinase function in a variety of cell types. This is attributed to the myddosome complex formed by IRAK-4 with myd88, IRAK-2, and IRAK-1 which by itself can cause the activation of downstream effector TRAF6 despite inhibition of the kinase domain of IRAK-4. With this challenge, several groups initiated the development of targeting protein degraders of IRAK-4 using Proteolysis-Targeting Chimeras (PROTACs) technology to completely remove the IRAK-4 from the cellular milieu. In this review, we will capture all these developments and the evolving science around this target.