2. Academic Validation
  3. Discovery of novel amidobenzimidazole derivatives as orally available small molecule modulators of stimulator of interferon genes for cancer immunotherapy

Discovery of novel amidobenzimidazole derivatives as orally available small molecule modulators of stimulator of interferon genes for cancer immunotherapy

  • Eur J Med Chem. 2023 Sep 30:261:115834. doi: 10.1016/j.ejmech.2023.115834.
Min Jae Jeon 1,  Hyelim Lee 2,  Seongman Jo 3,  Miso Kang 4,  Jeong Hyun Jeong 2,  So Hyeon Jeong 3,  Joo-Youn Lee 1,  Gyu Yong Song 5,  Hyunah Choo 2,  Sanghee Lee 6,  Hyejin Kim 7
Affiliations

Affiliations

  • 1 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 2 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
  • 3 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 4 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Department of Basic Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 5 Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 6 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Department for HY-KIST Bio-convergence, Hanyang University, Seoul, 04763, Republic of Korea. Electronic address: slee19@kist.re.kr.
  • 7 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. Electronic address: hjinkim@krict.re.kr.
PMID: 37862818 DOI: 10.1016/j.ejmech.2023.115834
Abstract

Stimulator of interferon genes (STING) agonists show promise as immunomodulatory agents for Cancer therapy. In this study, we report the discovery of a novel orally available STING agonist, SAP-04, that exhibits potent immunomodulatory effects for Cancer therapy. By optimizing the amidobenzimidazole core with various pyridine-based heterocyclic substituents, we identified a monomeric variant that displayed more efficient STING agonistic activity than the corresponding dimer. SAP-04 efficiently induced cytokine secretion related to innate immunity by directly binding of the compound to the STING protein, followed by sequential signal transduction for the STING signaling pathway and type I interferon (IFN) responses. Further pharmacological validation in vitro and in vivo demonstrated the potential utility of SAP-04 as an immunomodulatory agent for Cancer therapy in vivo. The in vivo Anticancer effect was observed in a 4T1 breast tumor syngeneic mouse model through oral administration of the compound. Our findings suggest a possible strategy for developing synthetically accessible monomeric variants as orally available STING agonists.

Keywords

Anti-cancer therapy; Immunomodulatory agent; Monomeric amidobenzimidazole; Oral administration; STING agonist; Stimulator of interferon genes.

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