RESUMEN
STING mediates innate immune responses that are triggered by the presence of cytosolic DNA. Activation of STING to boost antigen recognition is a therapeutic modality that is currently being tested in cancer patients using nucleic-acid based macrocyclic STING ligands. We describe here the discovery of 3,4-dihydroquinazolin-2(1H)-one based 6,6-bicyclic heterocyclic agonists of human STING that activate all known human variants of STING with high potency.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inmunidad Innata/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Neoplasias/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/síntesis química , Animales , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Citosol/química , ADN/química , Haplorrinos , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Unión Proteica , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
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 â¼10 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.
Asunto(s)
Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Proteínas de la Membrana/agonistas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Células Cultivadas , Citocinas/metabolismo , Descubrimiento de Drogas , Células HEK293 , Humanos , Proteínas de la Membrana/metabolismo , Oxindoles/química , Oxindoles/farmacología , Tiazinas/química , Tiazinas/farmacologíaRESUMEN
The cGAS/STING pathway initiates an innate immune response when DNA is detected in the cytosol. DNA bound cGAS synthesizes cyclic dinucleotides which bind and activate the adaptor STING, leading to downstream secretion of Type I interferons and other pro-inflammatory NFκB pathway cytokines. In the mouse, the STING driven innate immune response is central to immune based clearance of various tumors and this has triggered a significant effort focused on the discovery of human STING agonists for the treatment of cancer. This report uses an in vitro kinase assay to show that G10, a previously identified STING pathway activator is actually a weak but direct STING agonist and identifies other more potent leads.
Asunto(s)
Proteínas de la Membrana/metabolismo , Animales , Retículo Endoplásmico/metabolismo , Células HEK293 , Humanos , Factor 3 Regulador del Interferón/metabolismo , Proteínas de la Membrana/química , Ratones , Fosforilación , Dominios Proteicos , Estabilidad Proteica , Transducción de Señal , Células THP-1RESUMEN
Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.