2. Academic Validation
  3. Small molecule induced STING degradation facilitated by the HECT ligase HERC4

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

Affiliations

  • 1 Novartis BioMedical Research, Basel, Switzerland. merve.koch@novartis.com.
  • 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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