2. Academic Validation
  3. Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor

Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor

  • J Med Chem. 2022 Apr 14;65(7):5407-5432. doi: 10.1021/acs.jmedchem.1c01795.
Min Jae Jeon 1 2,  Hyelim Lee 3 4,  Jeehee Lee 3 5,  Soo Yeon Baek 3,  Donghee Lee 3,  Seongman Jo 1 6,  Joo-Youn Lee 1,  Miso Kang 3 4,  Hee Ra Jung 3 7,  Soo Bong Han 1 2,  Nam-Jung Kim 4 8,  Sanghee Lee 3 5,  Hyejin Kim 1
Affiliations

Affiliations

  • 1 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 2 Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea.
  • 3 Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 4 Department of Basic Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 5 Department for HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea.
  • 6 Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 7 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 8 Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
PMID: 35315650 DOI: 10.1021/acs.jmedchem.1c01795
Abstract

Stimulator of interferon genes (STING) is an endoplasmic reticulum-membrane protein that plays important roles in Cancer Immunotherapy by activating innate immune responses. We designed and synthesized STING modulators and characterized compounds 4a and 4c that share a crucial amidobenzimidazole moiety. In vitro STING binding and cell-based activity assays demonstrated the potency and efficacy of the compounds that function as direct STING agonists by stimulating STING downstream signaling and promoting type I interferon immune responses. In vitro metabolic studies and the pharmacokinetic properties of the compounds led us to investigate their Anticancer activity in an in vivo syngeneic model. Intravenous injection of compounds 4a and 4c significantly decreased tumor volume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived Cancer inhibition was observed in 4c-treated mouse models. The present results suggest the therapeutic potential of the compounds for Cancer Immunotherapy via STING-mediated immune activation.

Figures
Products