Discovery of APH02174 as a Highly Selective and Orally Bioavailable IRAK4 Degrader for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role as a key regulator in systemic inflammatory diseases, acting as a central mediator in the downstream signaling cascades of Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). Herein, we describe the design and synthesis of novel IRAK4 degraders based on a proteolysis-targeting chimera (PROTAC) strategy. Twenty-one PROTACs 3-5, 7-14, 22, 30-36 and 39 showed strong IRAK4 degradation (DC50 < 5 nM and Dmax > 85%), APH02174 (36) was identified as the lead compound exhibiting highly selective IRAK4 degradation in vitro and in vivo, along with favorable drug metabolism and oral pharmacokinetic properties. Further studies indicated that APH02174 demonstrated significant therapeutic efficacy by effectively alleviating imiquimod-induced psoriasis-like skin inflammation and antiarthritic activity in mouse models. These results highlight the potential of APH02174 as a highly selective and orally bioavailable IRAK4 PROTAC degrader in the treatment of inflammatory diseases mediated by IRAK4 signaling.