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.

中文翻译：

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基于间苯二酚的Grp94选择性抑制剂。

葡萄糖调节蛋白94（Grp94）是90 kDa热休克蛋白（Hsp90）家族的内质网居民，代表了治疗多种疾病的有希望的治疗靶标。Grp94是90 kDa热休克蛋白家族中最独特的成员，这是由于在其主要序列中插入了五个氨基酸，从而产生了Grp94专有的疏水亚口袋，可用于选择性抑制。已经开发出第一种利用疏水性S2亚口袋的基于间苯二酚的Grp94选择性抑制剂，并显示出低纳摩尔摩尔亲和力和对Grp94约10倍的选择性。此外，这些Grp94选择性抑制剂对多种骨髓瘤细胞表现出较低的微摩尔GI50值，支持Grp94作为治疗该疾病的新兴靶标。