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ACS Med Chem Lett. 2017 Sep 1;8(10):1013-1018. doi: 10.1021/acsmedchemlett.7b00193. eCollection 2017.

Resorcinol-Based Grp94-Selective Inhibitors.

Author information

  • 1Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, Kansas 66045, United States.
  • 2Warren Family Research Center for Drug Discovery and Development and Department of Chemistry & Biochemistry, University of Notre Dame, 305 McCourtney Hall, Notre Dame, Indiana 46556, United States.

Abstract

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.

KEYWORDS:

Grp94; Heat shock protein 90; cancer; multiple myeloma

PMID:
29057043
PMCID:
PMC5641966
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00193
[PubMed]
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