Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics

被引：95

作者：

Combs, AP ^{[1
]}

Yue, EW ^{[1
]}

Bower, M ^{[1
]}

Ala, PJ ^{[1
]}

Wayland, B ^{[1
]}

Douty, B ^{[1
]}

Takvorian, A ^{[1
]}

Polam, P ^{[1
]}

Wasserman, Z ^{[1
]}

Zhu, WY ^{[1
]}

Crawley, ML ^{[1
]}

Pruitt, J ^{[1
]}

Sparks, R ^{[1
]}

Glass, B ^{[1
]}

Modi, D ^{[1
]}

McLaughlin, E ^{[1
]}

Bostrom, L ^{[1
]}

Li, M ^{[1
]}

Galya, L ^{[1
]}

Blom, K ^{[1
]}

Hillman, M ^{[1
]}

Gonneville, L ^{[1
]}

Reid, BG ^{[1
]}

Wei, M ^{[1
]}

Becker-Pasha, M ^{[1
]}

Klabe, R ^{[1
]}

Huber, R ^{[1
]}

Li, YL ^{[1
]}

Hollis, G ^{[1
]}

Burn, TC ^{[1
]}

Wynn, R ^{[1
]}

Liu, P ^{[1
]}

Metcalf, B ^{[1
]}

机构：

[1] Incyte Corp, Discovery Chem, Expt Stn, Wilmington, DE 19880 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 21期

关键词：

D O I：

10.1021/jm0504555

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.

引用

页码：6544 / 6548

页数：5

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