Development of Small-Molecule STING Activators for Cancer Immunotherapy

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...

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Bibliographic Details
Published in:Biomedicines 2021-12, Vol.10 (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: Article
Language:English
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
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Summary: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.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines10010033