Small molecule induced STING degradation facilitated by the HECT ligase HERC4

Merve Mutlu (), Isabel Schmidt, Andrew I. Morrison, Benedikt Goretzki, Felix Freuler, Damien Begue, Oliver Simic, Nicolas Pythoud, Erik Ahrne, Sandra Kapps, Susan Roest, Debora Bonenfant, Delphine Jeanpierre, Thi-Thanh-Thao Tran, Rob Maher, Shaojian An, Amandine Rietsch, Florian Nigsch, Andreas Hofmann, John Reece-Hoyes, Christian N. Parker and Danilo Guerini
Additional contact information
Merve Mutlu: Novartis BioMedical Research
Isabel Schmidt: Novartis BioMedical Research
Andrew I. Morrison: Novartis BioMedical Research
Benedikt Goretzki: Novartis BioMedical Research
Felix Freuler: Novartis BioMedical Research
Damien Begue: Novartis BioMedical Research
Oliver Simic: Novartis BioMedical Research
Nicolas Pythoud: Novartis BioMedical Research
Erik Ahrne: Novartis BioMedical Research
Sandra Kapps: Novartis BioMedical Research
Susan Roest: Novartis BioMedical Research
Debora Bonenfant: Novartis BioMedical Research
Delphine Jeanpierre: Novartis BioMedical Research
Thi-Thanh-Thao Tran: Novartis BioMedical Research
Rob Maher: Novartis BioMedical Research
Shaojian An: Novartis BioMedical Research
Amandine Rietsch: Novartis BioMedical Research
Florian Nigsch: Novartis BioMedical Research
Andreas Hofmann: Novartis BioMedical Research
John Reece-Hoyes: Novartis BioMedical Research
Christian N. Parker: Novartis BioMedical Research
Danilo Guerini: Novartis BioMedical Research

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48922-w

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