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.