Article
作者: An, Shaojian ; Maher, Rob ; Morrison, Andrew I ; Bonenfant, Debora ; Simic, Oliver ; Freuler, Felix ; Hofmann, Andreas ; Roest, Susan ; Begue, Damien ; Kapps, Sandra ; Nigsch, Florian ; Pythoud, Nicolas ; Ahrne, Erik ; Mutlu, Merve ; Tran, Thi-Thanh-Thao ; Goretzki, Benedikt ; Schmidt, Isabel ; Rietsch, Amandine ; Guerini, Danilo ; Parker, Christian N ; Jeanpierre, Delphine ; Reece-Hoyes, John
Abstract:Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its’ involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING, suggesting potential therapeutic applications.