Development of Small-Molecule STING Activators for Cancer Immunotherapy

• Published in: Biomedicines Vol. 10; no. 1; p. 33
• Main Authors: Jung, Hee Ra, Jo, Seongman, Jeon, Min Jae, Lee, Hyelim, Chu, Yeonjeong, Lee, Jeehee, Kim, Eunha, Song, Gyu Yong, Jung, Cheulhee, Kim, Hyejin, Lee, Sanghee
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-12-2021; MDPI
• Subjects: Antitumor agents; Cancer; Cancer immunotherapy; Cyclic GMP; Immune response; Immunotherapy; Innate immunity; Interferon; Kinases; Membranes; Phosphatase; Phosphorylation; Proteins; Response rates; STING; STING activator; Tumors; type I interferon; United States > US; type I interferon; STING; STING activator; cancer immunotherapy
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines10010033

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.