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Small molecule induced STING degradation facilitated by the HECT ligase HERC4

Mutlu, Merve, Schmidt, Isabel, Morrison, Andrew I., Goretzki, Benedikt, Freuler, Felix, Begue, Damien, Simic, Oliver, Pythoud, Nicolas, Ahrne, Erik, Kapps-Fouthier, Sandra, Roest, Susan, Bonenfant, Debora, Jeanpierre, Delphine, Tran, Thi-Thanh-Thao, Maher, Rob, An, Shaojian, Rietsch, Amandine, Nigsch, Florian, Hofmann, Andreas, Reece-Hoyes, John, Parker, Christian and Guerini, Danilo (2024) Small molecule induced STING degradation facilitated by the HECT ligase HERC4. Nature communications, 15 (1). p. 4584. ISSN 2041-1723


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 field of TPD and a compound-induced degradation of STING, suggesting potential therapeutic applications.

Item Type: Article
Keywords: STING, small molecule degrader, targeted protein degradation, TPD, MGD, glue degrader, HERC4
Date Deposited: 14 Jun 2024 00:45
Last Modified: 14 Jun 2024 00:46