Abstract
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.
Keywords:
Immune oncology; Innate immunity; Interferon; STING; cGAS.
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cytosol / chemistry
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DNA / chemistry
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Haplorhini
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Humans
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Immunity, Innate / drug effects*
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred BALB C
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Neoplasms / drug therapy*
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Protein Binding
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Signal Transduction
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Small Molecule Libraries / chemical synthesis*
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Small Molecule Libraries / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Membrane Proteins
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STING1 protein, human
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Small Molecule Libraries
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DNA