2. Academic Validation
  3. Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy

Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy

  • Angew Chem Int Ed Engl. 2023 Apr 24;62(18):e202300978. doi: 10.1002/anie.202300978.
Wansang Cho 1,  Solchan Won 2 3,  Yoona Choi 1,  Sihyeong Yi 1,  Jong Beom Park 1,  Jun-Gyu Park 2 3,  Caroline E Kim 1,  Chintam Narayana 1,  Ju Hee Kim 4,  Junhyeong Yim 5,  Young Il Choi 4,  Dong-Sup Lee 2 3,  Seung Bum Park 1 5 4
Affiliations

Affiliations

  • 1 Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, 08826, Korea.
  • 2 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • 3 Department of Biomedical Sciences, Wide River Institute of Immunology, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • 4 SPARK Biopharma, Inc., Seoul, 08791, Korea.
  • 5 Department of Biophysics and Chemical Biology, Seoul National University, Seoul, 08826, Korea.
PMID: 36827625 DOI: 10.1002/anie.202300978
Abstract

Modulating target proteins via the ubiquitin-proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING-TRIM29 E3 Ligase interaction, thus blocking TRIM29-induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti-PD-1 antibody via systemic Anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno-oncology.

Keywords

Anticancer Agents; Immunotherapy; Protein-Protein Interaction; STING; Targeted Protein Upregulation.

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