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鉴定和优化 4-苯胺喹啉类化合物作为细胞周期蛋白 G 相关激酶抑制剂。

Identification and Optimization of 4-Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase.

机构信息

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland.

出版信息

ChemMedChem. 2018 Jan 8;13(1):48-66. doi: 10.1002/cmdc.201700663. Epub 2017 Nov 27.

DOI:10.1002/cmdc.201700663
PMID:29072804
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5914168/
Abstract

4-Anilinoquinolines were identified as potent and narrow-spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000-fold selectivity relative to other members of the numb-associated kinase (NAK) subfamily, and a compound (6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine; 49) with a narrow-spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases.

摘要

4-苯胺喹啉类化合物被鉴定为细胞周期蛋白 G 相关激酶（GAK）的有效且具有窄谱抑制作用的物质，GAK 是一种重要的宿主细胞中病毒和细菌进入的调节因子。对 4-苯胺基团和 6,7-喹啉取代基进行优化，得到了对 GAK 具有纳摩尔活性的抑制剂，相对于 numb 相关激酶（NAK）亚家族的其他成员具有超过 50,000 倍的选择性，并且一种化合物（6,7-二甲氧基-N-（3,4,5-三甲氧基苯基）喹啉-4-胺；49）具有窄谱激酶组谱。这些化合物可能是探索 GAK 在预防广泛的传染性和系统性疾病方面的治疗潜力的有用工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/4916c4944e58/nihms957779f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/938094597d85/nihms957779f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/07943aa43923/nihms957779f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/4916c4944e58/nihms957779f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/347879419d22/nihms957779f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/f21a46833568/nihms957779f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/cb8ce9ead90a/nihms957779f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/d2724aba70c0/nihms957779f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/938094597d85/nihms957779f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/07943aa43923/nihms957779f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8259/5914168/4916c4944e58/nihms957779f7.jpg

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