Using small molecules to target protein phosphatases

被引:47
|
作者
Vintonyak, Viktor V. [1 ]
Waldmann, Herbert [1 ,2 ]
Rauh, Daniel [2 ,3 ]
机构
[1] Max Planck Inst Mol Physiol, D-44227 Dortmund, Germany
[2] Tech Univ Dortmund, D-44221 Dortmund, Germany
[3] Max Planck Soc, Chem Genom Ctr, D-44227 Dortmund, Germany
关键词
Inhibitor; Structure; Drug; Design; BIOLOGY-ORIENTED SYNTHESIS; STRUCTURE-BASED DESIGN; SOLID-PHASE SYNTHESIS; CELL-CYCLE ARREST; TYROSINE-PHOSPHATASE; MYCOBACTERIUM-TUBERCULOSIS; PTP1B INHIBITORS; CANCER-CELLS; INSULIN SENSITIVITY; CDC25; PHOSPHATASES;
D O I
10.1016/j.bmc.2011.02.047
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The site specific functionalization of phosphate groups with amino acid side chains of substrate proteins represents one of the most important regulatory mechanisms of biological systems. Phosphorylation and dephosphorylation are reversibly catalyzed by protein kinases and protein phosphatases, and the aberrant regulation of these enzymes is associated with the onset and progression of various disease states such as cancer, diabetes, neurodegenerative and autoimmune disorders, making these proteins attractive targets for drug discovery. Here we report on strategies currently explored for the identification and development of various inhibitors directed against clinically relevant phosphatases. While over the last years, inhibition of phosphorylation has evolved into a key strategy in targeted therapies, the development of clinically relevant phosphatase inhibitors still faces major bottlenecks and is often plagued by limited selectivity and unfavorable pharmacokinetics. The reader will gain a better understanding of the importance of the field and its current limitations. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2145 / 2155
页数:11
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