Development of Small-Molecule STING Activators for Cancer Immunotherapy

  • Biomedicines. 2021 Dec 24;10(1):33. doi: 10.3390/biomedicines10010033.
Hee Ra Jung  1  2 ,  Seongman Jo  3  4 ,  Min Jae Jeon  3  5 ,  Hyelim Lee  1  6 ,  Yeonjeong Chu  1  7 ,  Jeehee Lee  1  8 ,  Eunha Kim  7 ,  Gyu Yong Song  4 ,  Cheulhee Jung  2 ,  Hyejin Kim  3 ,  Sanghee Lee  1  8
Affiliations
  • 1. Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea.
  • 2. Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea.
  • 3. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.
  • 4. Department of Pharmacy, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
  • 5. Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Korea.
  • 6. Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.
  • 7. Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea.
  • 8. Department of HY-KIST Bio-Convergence, Hanyang University, Seoul 04763, Korea.
PMID: 35052713 DOI: 10.3390/biomedicines10010033
Abstract

In Cancer Immunotherapy, the cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from 'cold' to 'hot' through the activation of the type I interferon response. To develop a new chemical entity for STING Activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in Cancer treatment.

Keywords
STING; STING activator; cancer immunotherapy; type I interferon.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-165152
    KAS 08
    99.9%, Biochemical Reagent
    target: STING
    Research Areas: Others