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.
Funding: This research was funded by the Korea Institute of Science and Technology Institutional Program (2E30952 and 2E30956), Korea Research Institute of Chemical Technology (KK2032–00), and National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2019M3E5D4066905, 2020R1C1C1003736, and 2021R1C1C1005134). APC was funded by 2E30956.This research was funded by the Korea Institute of Science and Technology Institutional Program (2E30952 and 2E30956), Korea Research Institute of Chemical Technology (KK2032–00), and National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (NRF-2019M3E5D4066905, 2020R1C1C1003736, and 2021R1C1C1005134). APC was funded by 2E30956. The chemical library used in this study was kindly provided by the Korea Chemical Bank (www.chembank.org, accessed on 20 November 2021) of the Korea Research Institute of Chemical Technology (KRICT). We would like to thank Sang-Hun Jung at Chungnam National University for donating sulfonyl-pyrrolidine analogs to the Korea Chemical Bank.
