Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors

被引:33
作者
He, Yantao [1 ]
Zeng, Li-Fan [1 ]
Yu, Zhi-Hong [1 ]
He, Rongjun [1 ]
Liu, Sijiu [1 ]
Zhang, Zhong-Yin [1 ]
机构
[1] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA
基金
美国国家卫生研究院;
关键词
Protein tyrosine phosphatases; Therapeutic target; Salicylic acid; Inhibitor specificity; Bioavailability; Combinatorial chemistry; JUVENILE MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; SUBSTRATE-SPECIFICITY; CLICK CHEMISTRY; MOLECULAR-BASIS; IN-SITU; MYCOBACTERIUM-TUBERCULOSIS; COMBINATORIAL SYNTHESIS; RHEUMATOID-ARTHRITIS; INSULIN SENSITIVITY;
D O I
10.1016/j.bmc.2011.11.004
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
Protein tyrosine phosphatases (PTPs) constitute a large and structurally diverse family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. Malfunction of PTP activity has significant implications in many human diseases, and the PTP protein family provides an exciting array of validated diabetes/obesity (PTP1B), oncology (SHP2), autoimmunity (Lyp), and infectious disease (mPTPB) targets. However, despite the fact that PTPs have been garnering attention as novel therapeutic targets, they remain largely an untapped resource. The main challenges facing drug developers by the PTPs are inhibitor specificity and bioavailability. Work over the last ten years has demonstrated that it is feasible to develop potent and selective inhibitors for individual members of the PTP family by tethering together small ligands that can simultaneously occupy both the active site and unique nearby peripheral binding sites. Recent results with the bicyclic salicylic acid pharmacophores indicate that the new chemistry platform may provide a potential solution to overcome the bioavailability issue that has plagued the PTP drug discovery field for many years. Structural analysis of PTP-inhibitor complexes reveals molecular determinants important for the development of more potent and selective PTP inhibitors, thus offering hope in the medicinal chemistry of a largely unexploited protein class with a wealth of attractive drug targets. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1940 / 1946
页数:7
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