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 <b>3</b>-<b>5</b>, <b>7</b>-<b>14</b>, <b>22</b>, <b>30</b>-<b>36</b> and <b>39</b> showed strong IRAK4 degradation (DC₅₀ < 5 nM and <i>D</i>_max > 85%), <b>APH02174</b> (<b>36</b>) was identified as the lead compound exhibiting highly selective IRAK4 degradation <i>in vitro</i> and <i>in vivo</i>, along with favorable drug metabolism and oral pharmacokinetic properties. Further studies indicated that <b>APH02174</b> 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 <b>APH02174</b> as a highly selective and orally bioavailable IRAK4 PROTAC degrader in the treatment of inflammatory diseases mediated by IRAK4 signaling.