Targeting inactive enzyme conformation: aryl diketoacid derivatives as a new class of PTP1B inhibitors.
Targeting inactive enzyme conformation: aryl diketoacid derivatives as a new class of PTP1B inhibitors.
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DOI：
10.1021/ja8068177
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发表时间：
2008-12-17
影响因子：
15
通讯作者：
Zhang ZY
中科院分区：
文献类型：
--
作者：
Liu S;Zeng LF;Wu L;Yu X;Xue T;Gunawan AM;Long YQ;Zhang ZY
蛋白酪氨酸磷酸酶1B（PTP1B）作为糖尿病、肥胖症以及癌症的治疗靶点已经引起了相当大的兴趣。鉴定具有良好生物利用度的抑制性化合物是针对PTP的药物发现计划的主要挑战。目前大多数PTP活性位点导向的药效团是带负电荷的pTyr模拟物，其不能容易地进入细胞。这种细胞渗透性的缺乏限制了此类化合物在信号传导研究和进一步治疗开发中的效用。我们确定芳基二酮酸作为新的pTyr替代品，并表明中性酰胺连接的芳基二酮酸二聚体也表现出优异的PTP抑制活性。动力学研究表明，这些芳基二酮酸衍生物作为PTP1B的非竞争性抑制剂。配体结合的PTP1B的晶体结构表明，无论是芳基二酮酸及其二聚衍生物结合PTP1B的活性位点，虽然有不同的相互作用模式，在催化失活，WPD环开放构象。此外，二聚芳基二酮酸是细胞可渗透的，并增强肝癌细胞中的胰岛素信号传导，这表明靶向非活性构象可能为创建具有改善的药理学特性的活性位点定向的PTP1B抑制剂提供独特的机会。
There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.
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影响因子：
3.6
作者：
Jiang, XH;Song, LD;Long, YQ
通讯作者：
Long, YQ
影响因子：
2.9
作者：
Juszczak, LJ;Zhang, ZY;Eads, DD
通讯作者：
Eads, DD
影响因子：
30.8
作者：
Julien, Sofi G.;Dube, Nadia;Tremblay, Michel L.
通讯作者：
Tremblay, Michel L.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
4.8
作者：
Bjorge, JD;Pang, A;Fujita, DJ
通讯作者：
Fujita, DJ