Biomedicines · 2021 · 11 citations · 35 references
Life SciencesMedicinal ChemistryOncologyImmunotherapyInnate ImmunitySignal TransductionCancer ImmunotherapyCombination ImmunotherapyImmune Cell SignalingInnate Immune ModulationInnate Immune Signaling PathwaysInterferon ResponsesCombination TherapyCyclic Gmp-amp Synthase SignalingInnate Antitumor ImmunityInterferon Pathway GenesInterferon-stimulated GenesSmall-molecule ActivatorsSting PathwayType I Interferon Pathways
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.
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Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation
Siqi Liu, Xin Cai, Jiaxi Wu et al. · Science · 2015 · 1.9K citations