A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling.
A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling.
复制标题
DOI：
10.1021/acschembio.7b01060
复制
发表时间：
2018-04-20
影响因子：
4
通讯作者：
Mitchison T
中科院分区：
文献类型：
--
作者：
Koch PD;Miller HR;Yu G;Tallarico JA;Sorger PK;Wang Y;Feng Y;Thomas JR;Ross NT;Mitchison T
我们筛选了一个生物活性小分子文库，通过IRF3和NFkB途径激活和抑制天然免疫信号，目的是促进对途径的理解，并发现免疫学研究的探针。我们使用高含量筛选来测量原代人巨噬细胞中IRF3和NFkB的胞浆到胞核的移位；这些转录因子在刺痛和其他促炎途径的激活中发挥关键作用。我们的途径激活剂筛选产生了一组不同的HIT，促进了IRF3和/或NFkB的核转位，但这些化合物中的大多数不会引起下游途径的激活。对刺痛通路拮抗剂的筛选产生了多种激酶抑制剂，其中一些抑制了以前未知的调节该通路活性的激酶。结构-活性关系(SAR)和随后的化学蛋白质组学实验表明，MAPKAPK5(PRAK)是一种调节IRF3在人巨噬细胞中转位的激酶。我们的工作建立了一种高含量的筛选方法来测量人巨噬细胞中的促炎途径，并确定了抑制这种途径的新方法；在筛选的目标中有几个分子可能值得进一步开发作为抗炎药物。
We screened a library of bioactive small molecules for activators and inhibitors of innate immune signaling through IRF3 and NFkB pathways with the goals of advancing pathway understanding and discovering probes for immunology research. We used high content screening to measure the translocation from the cytoplasm to nucleus of IRF3 and NFkB in primary human macrophages; these transcription factors play a critical role in the activation of STING and other pro-inflammatory pathways. Our pathway activator screen yielded a diverse set of hits that promoted nuclear translocation of IRF3 and/or NFkB, but the majority of these compounds did not cause activation of downstream pathways. Screening for antagonists of the STING pathway yielded multiple kinase inhibitors, some of which inhibit kinases not previously known to regulate the activity of this pathway. Structure-activity relationships (SAR) and subsequent chemical proteomics experiments suggested that MAPKAPK5 (PRAK) is a kinase that regulates IRF3 translocation in human macrophages. Our work establishes a high content screening approach for measuring pro-inflammatory pathways in human macrophages and identifies novel ways to inhibit such pathways; among the targets of the screen are several molecules that may merit further development as anti-inflammatory drugs.
登录
查看更多内容
DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
6.4
作者：
Pryke KM;Abraham J;Sali TM;Gall BJ;Archer I;Liu A;Bambina S;Baird J;Gough M;Chakhtoura M;Haddad EK;Kirby IT;Nilsen A;Streblow DN;Hirsch AJ;Smith JL;DeFilippis VR
通讯作者：
DeFilippis VR
影响因子：
4.8
作者：
Ehlting, Christian;Ronkina, Natalia;Bode, Johannes G.
通讯作者：
Bode, Johannes G.
影响因子：
8.8
作者：
Gonugunta VK;Sakai T;Pokatayev V;Yang K;Wu J;Dobbs N;Yan N
通讯作者：
Yan N
影响因子：
17.1
作者：
Fu J;Kanne DB;Leong M;Glickman LH;McWhirter SM;Lemmens E;Mechette K;Leong JJ;Lauer P;Liu W;Sivick KE;Zeng Q;Soares KC;Zheng L;Portnoy DA;Woodward JJ;Pardoll DM;Dubensky TW Jr;Kim Y
通讯作者：
Kim Y