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

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 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
URI:	https://oak.novartis.com/id/eprint/53199