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Optimization of Isothiazolo[4,3-b]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral Activity
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2018-06-28 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00613
Szu-Yuan Pu 1 , Randy Wouters 2 , Stanford Schor 1 , Jef Rozenski 2 , Rina Barouch-Bentov 1 , Laura I. Prugar 3 , Cecilia M. O’Brien 3 , Jennifer M. Brannan 3 , John M. Dye 3 , Piet Herdewijn 2 , Steven De Jonghe 2 , Shirit Einav 1
Affiliation  

There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-associated kinase (GAK), a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3-b]pyridines that maintain high GAK affinity and selectivity. These compounds demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.

中文翻译:

具有广谱抗病毒活性的基于异噻唑并[4,3 - b ]吡啶的Cyclin G相关激酶(GAK)抑制剂的优化

迫切需要制定战略来对抗登革热和其他新兴的病毒感染。我们报道细胞周期蛋白G相关激酶(GAK),网格蛋白相关宿主衔接蛋白AP-1和AP-2的细胞调节剂,在病毒生命周期的早期和晚期调节多种无关RNA病毒的细胞内运输。我们还报告了基于异噻唑并[4,3- b ]吡啶骨架的有效,选择性GAK抑制剂的发现,尽管具有中等抗病毒活性。在这里,我们描述了我们为发现新型异噻唑啉[4,3- b]所做的努力。维持高GAK亲和力和选择性的]吡啶。这些化合物表现出改善的抗登革热病毒(包括人原代树突状细胞)的体外活性,以及​​抗无关埃博拉病毒和基孔肯雅病毒的功效。此外,已证实抑制GAK活性是这些化合物抗病毒作用的重要机制。这些发现表明,以GAK为靶标的广谱方法可用于对抗目前无法治愈的新兴病毒感染。
更新日期:2018-06-28
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