公开(公告)号：US20170146519A1

公开(公告)日：2017-05-25

申请号：US15357685

申请日：2016-11-21

申请人： Victor DeFilippis ,  Tina Sali ,  Kara Pryke ,  Jinu Abraham ,  Andrew Liu ,  Iris Archer ,  Kayla Sheridan ,  Aaron Nilsen ,  Rebecca Broeckel ,  Jessica Smith ,  Lisi Amsler ,  Daniel Streblow ,  Andrew Placzek

发明人： Victor DeFilippis ,  Tina Sali ,  Kara Pryke ,  Jinu Abraham ,  Andrew Liu ,  Iris Archer ,  Kayla Sheridan ,  Aaron Nilsen ,  Rebecca Broeckel ,  Jessica Smith ,  Lisi Amsler ,  Daniel Streblow ,  Andrew Placzek

IPC分类号： G01N33/50 ,  C07D279/16 ,  C07D417/12

CPC分类号： G01N33/5041 ,  A61K31/5415 ,  C07D279/16 ,  C07D417/12 ,  G01N2333/705 ,  Y02A50/382

摘要： 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.