Small molecule induced STING degradation facilitated by the HECT ligase HERC4

Area of Science:

• Immunology and Molecular Biology
• Drug Discovery and Pharmacology

Background:

• Stimulator of Interferon Genes (STING) is crucial in sensing nucleic acids and regulating type I interferon responses.
• STING's role in health and disease makes it a significant target for drug development.
• Targeted Protein Degradation (TPD) offers a new strategy to target proteins previously considered undruggable.

Purpose of the Study:

• To identify novel small molecules capable of degrading STING.
• To explore the potential of TPD for targeting STING and its pathological mutations.

Main Methods:

• Identification of a novel STING degrader, AK59.
• Characterization of AK59's mechanism involving HERC4, a HECT-domain E3 ligase.
• Evaluation of AK59's efficacy against common pathological STING mutations.

Main Results:

• AK59 was identified as a potent degrader of STING.
• The degradation process mediated by AK59 utilizes the HERC4 E3 ligase.
• AK59 demonstrated effectiveness against prevalent pathological STING mutations.

Conclusions:

• AK59 represents a novel therapeutic strategy for STING-mediated diseases via targeted protein degradation.
• The findings introduce HERC4 as a key player in compound-induced STING degradation.
• This approach holds potential for clinical applications, particularly for diseases involving mutated STING.