Small molecule induced STING degradation facilitated by the HECT ligase HERC4

  • Nat Commun. 2024 May 29;15(1):4584. doi: 10.1038/s41467-024-48922-w.
Merve Mutlu  1 ,  Isabel Schmidt  2 ,  Andrew I Morrison  2  3 ,  Benedikt Goretzki  2 ,  Felix Freuler  2 ,  Damien Begue  2 ,  Oliver Simic  2 ,  Nicolas Pythoud  2 ,  Erik Ahrne  2 ,  Sandra Kapps  2 ,  Susan Roest  2 ,  Debora Bonenfant  2  4 ,  Delphine Jeanpierre  2 ,  Thi-Thanh-Thao Tran  2 ,  Rob Maher  5 ,  Shaojian An  5 ,  Amandine Rietsch  2 ,  Florian Nigsch  2 ,  Andreas Hofmann  2 ,  John Reece-Hoyes  5  6 ,  Christian N Parker  2 ,  Danilo Guerini  2
Affiliations
  • 1. Novartis BioMedical Research, Basel, Switzerland. [email protected].
  • 2. Novartis BioMedical Research, Basel, Switzerland.
  • 3. Amsterdam UMC location Vrije Universiteit Amsterdam, Molecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, De Boelelaan, 1117, Amsterdam, The Netherlands.
  • 4. Monte Rosa Therapeutics, Basel, Switzerland.
  • 5. Novartis BioMedical Research, Cambridge, MA, USA.
  • 6. Vector Biology, Cambridge, MA, USA.
PMID: 38811577 DOI: 10.1038/s41467-024-48922-w
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.

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