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.
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。
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本文引用的文献
1
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PLoS One. 2017 Aug 2;12(8):e0181585. doi: 10.1371/journal.pone.0181585. eCollection 2017.
2
The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.6-(叔丁基磺酰基)-N-(5-氟-1H-吲唑-3-基)喹啉-4-胺（GSK583）的鉴定及药理特性研究，一种高效且选择性的RIP2激酶抑制剂
J Med Chem. 2016 May 26;59(10):4867-80. doi: 10.1021/acs.jmedchem.6b00211. Epub 2016 May 4.
3
The Emergence of Zika Virus as a Global Health Security Threat: A Review and a Consensus Statement of the INDUSEM Joint working Group (JWG).寨卡病毒成为全球卫生安全威胁：INDUSEM联合工作组（JWG）的综述与共识声明
J Glob Infect Dis. 2016 Jan-Mar;8(1):3-15. doi: 10.4103/0974-777X.176140.
4
Endocytic control of signaling at the plasma membrane.质膜信号传导的内吞控制
Curr Opin Cell Biol. 2016 Apr;39:21-7. doi: 10.1016/j.ceb.2016.01.012. Epub 2016 Feb 10.
5
Family-wide Structural Analysis of Human Numb-Associated Protein Kinases.人类麻木相关蛋白激酶的全家族结构分析
Structure. 2016 Mar 1;24(3):401-11. doi: 10.1016/j.str.2015.12.015. Epub 2016 Feb 4.
6
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Nat Commun. 2015 Dec 3;6:10091. doi: 10.1038/ncomms10091.
7
KLIFS: a structural kinase-ligand interaction database.KLIFS：一个结构激酶-配体相互作用数据库。
Nucleic Acids Res. 2016 Jan 4;44(D1):D365-71. doi: 10.1093/nar/gkv1082. Epub 2015 Oct 22.
8
Application of BRET to monitor ligand binding to GPCRs.应用生物发光共振能量转移技术监测配体与G蛋白偶联受体的结合
Nat Methods. 2015 Jul;12(7):661-663. doi: 10.1038/nmeth.3398. Epub 2015 Jun 1.
9
NanoBRET--A Novel BRET Platform for the Analysis of Protein-Protein Interactions.纳米生物发光共振能量转移——一种用于分析蛋白质-蛋白质相互作用的新型生物发光共振能量转移平台。
ACS Chem Biol. 2015 Aug 21;10(8):1797-804. doi: 10.1021/acschembio.5b00143. Epub 2015 Jun 9.
10
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