Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents,Journal of Medicinal Chemistry

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Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-04-09 00:00:00 , DOI: 10.1021/jm501759m
Sona Kovackova _{1,

2} , Lei Chang _{1,

2} , Elena Bekerman ₃ , Gregory Neveu ₃ , Rina Barouch-Bentov ₃ , Apirat Chaikuad ₄ , Christina Heroven ₄ , Michal Šála _{1,

2} , Steven De Jonghe _{1,

2} , Stefan Knapp ₄ , Shirit Einav ₃ , Piet Herdewijn _{1,

2}

Affiliation

Cyclin G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystallization experiments revealed that these compounds behaved as classic type I ATP-competitive kinase inhibitors. In addition, we have demonstrated that these compounds exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chemical probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer, and Parkinson’s disease).

中文翻译：

细胞周期蛋白 G 相关激酶 (GAK) 选择性抑制剂作为抗丙型肝炎药物

细胞周期蛋白 G 相关激酶 (GAK) 成为治疗病毒感染的有前景的药物靶点。然而，迄今为止，文献中尚未报道有效且选择性的 GAK 抑制剂。本文介绍了异噻唑并[5,4- b ]吡啶作为选择性 GAK 抑制剂的发现，其中最有效的同系物对 GAK 表现出低纳摩尔级的结合亲和力。共结晶实验表明这些化合物是经典的 I 型 ATP 竞争性激酶抑制剂。此外，我们还证明这些化合物通过抑制丙型肝炎病毒（HCV）生命周期中两个时间上不同的步骤（即病毒进入和组装）而表现出有效的抗丙型肝炎病毒（HCV）活性。因此，这些 GAK 抑制剂代表了化学探针，可用于研究 GAK 在涉及 GAK 的不同疾病领域（包括病毒感染、癌症和帕金森病）中的功能。

更新日期：2015-04-09

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