(Curadev) Intravenous administration of the small molecule STING agonist CRD5500 elicits potent anti-tumor immune responses in cold tumors

hSTING & anti-tumor response in cold tumors

April 8, 2022


The adaptor protein STING plays a major role in innate immune sensing of cytosolic nucleic acids, by triggering a robust interferon response. Despite the importance of this protein as a potential therapeutic target for serious unmet medical conditions including cancer and infectious disease there remains a paucity of STING ligands. Starting with a benzothiazinone series of weak STING activators (human EC50 ∼10 μM) we identified several chemotypes with sub-micromolar STING activity across all the major protein polymorphs. An example compound 53 based on an oxindole core structure demonstrated robust on-target functional activation of STING (human EC50 185 nM) in immortalised and primary cells and a cytokine induction fingerprint consistent with STING activation. Our study has identified several related series of potent small molecule human STING activators with potential to be developed as immunomodulatory therapeutics.

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The hSTING mouse enables the in vivo assessment of agents and therapies targeting the human STING in fully immunocompetent mice.

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