Discovery of a Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Using a Linked-Fragment Strategy
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- 作者：Bruce G. Szczepankiewicz ; Gang Liu ; Philip J. Hajduk ; Cele Abad-Zapatero ; Zhonghua Pei ; Zhili Xin ; Thomas H. Lubben ; James M. Trevillyan ; Michael A. Stashko ; Stephen J. Ballaron ; Heng Liang ; Flora Hua
- 刊名：Journal of the American Chemical Society
- 出版年：2003
- 出版时间：April 9, 2003
- 年：2003
- 卷：125
- 期：14
- 页码：4087 - 4096
- 全文大小：476K
- 年卷期：v.125,no.14(April 9, 2003)
- ISSN：1520-5126
文摘
Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor.Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitorsto treat type II diabetes has received considerable attention. In this work, NMR-based screening identifieda nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-basedscreening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that theinhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayedexcellent potency and good selectivity over many other phosphatases. The modular approach to drug designdescribed in this work should be applicable for the design of potent and selective inhibitors of othertherapeutically relevant protein tyrosine phosphatases.