Design, Synthesis, and Evaluation of Nucleolin-Bridged, MDM2-Recruiting IRAK4 Degraders for the Treatment of Autoimmune Diseases.

IRAK4 plays a pivotal role in autoimmune diseases by exerting both kinase and scaffolding functions. Conventional inhibitors of IRAK4 target its kinase activity while leaving the scaffolding function intact. PROTACs, which induce the complete degradation of target proteins, offer a promising strategy to overcome the constraints of traditional inhibition. Here, we designed and synthesized a series of nucleolin (NCL)-bridged, MDM2-recruiting PROTAC degraders by conjugating oridonin (Ori) with Zimlovisertib (Zim). Structure-activity relationship studies identified Ori-Zim-6 as the most potent degrader. Mechanistic investigations revealed that Ori-Zim-6 triggered the proteasomal degradation of IRAK4. Ori-Zim-6 effectively inhibited pro-inflammatory response across multiple cell types in vitro. In a mouse model of psoriasis, oral administration of Ori-Zim-6 resulted in robust therapeutic efficacy and a favorable safety profile. Notably, Ori-Zim-6 exhibited superior anti-inflammatory activity compared to the reference degrader KT-474. These findings establish Ori-Zim-6 as an orally available IRAK4 degrader for the treatment of autoimmune diseases.