STING AGONISTS AND METHODS OF SELECTING STING AGONISTS
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United States of America Patent
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Nov 21, 2016
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Nov 20, 2015
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Abstract
Disclosed are small molecules capable of activating the type I interferon (IFN) response by way of the transcription factor IFN regulatory factor 3 (IRF3) were identified. A high throughput in vitro screen yielded 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (referred to herein as G10), which was found to trigger IRF3/IFN-associated transcription in human fibroblasts. To define cellular proteins essential to elicitation of the antiviral activity by the compound a reverse genetics approach that utilized genome editing via CRISPR/Cas9 technology was employed. This allowed the identification of IRF3, the IRF3-activating adaptor molecule STING, and the IFN-associated transcription factor STAT1 as required for observed gene induction and antiviral effects.
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