Resorcinol-Based Grp94-Selective Inhibitors

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作   者：

Anuj Khandelwal;  Vincent M. Crowley;  Brian S. J. Blagg; 

作者机构：

Notre Dame;  Indiana 46556;  Warren Family Research Center for Drug Discovery and Development and Department of Chemistry & Biochemistry;  United States;  1251 Wescoe Hall Drive;  Lawrence;  305 McCourtney Hall;  Kansas 66045;  The University of Kansas;  Malott Hall 4070;  University of Notre Dame;  Department of Medicinal Chemistry; 

关键词：

multiple myeloma;  cancer;  Grp94;  Heat shock protein 90; 

期刊名称：

ACS medicinal chemistry letters

i s s n：

1948-5875

年卷期：

2017 年 8 卷 10 期

页   码：

1013-1018

页   码：

摘   要：

Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the 90 kDa heat shock protein (Hsp90) family and represents a promising therapeutic target for the treatment of several diseases. Grp94 is the most unique member of the 90 kDa heat shock protein family due to a five amino acid insertion into its primary sequence, which creates hydrophobic subpockets exclusive to Grp94 that can be utilized for selective inhibition. The first resorcinol-based Grp94-selective inhibitor to take advantage of the hydrophobic S2 subpocket has been developed and shown to manifest low nanomolar affinity and ∼10-fold selectivity for Grp94. Furthermore, these Grp94-selective inhibitors manifest low micromolar GI50 values against multiple myeloma cells, supporting Grp94 as an emerging target for the treatment of this disease.