Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs.

Interleukin-1 receptor associated kinase 4 (IRAK4) is a promising therapeutic target for diffuse large B-cell lymphoma driven by MYD88 L265P mutant, acting both as a kinase and a scaffolding protein for downstream signaling molecules. While previous efforts to modulate IRAK4 activity with kinase inhibitors alone displayed moderate efficacy, protein degradation may offer a solution to blocking both IRAK4 kinase activity and scaffolding capabilities. To this end, the potent IRAK4 degrader was discovered, and it effectively inhibited the activation of downstream NF-κB signaling and outperformed the parent compound . In addition, compound displayed a substantial advantage in reduction of the viability of OCI-LY10 and TMD8 cells over the parent compound . These results underline the potential that eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.