The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with pan-Hsp90 Inhibition. Kent, Vitumbiko Munthali, John Koren, III, John A Taylor, III, Leonard M. Mishra, Weiya Liu, Kristin Beebe, Monimoy Banerjee, Caitlin N. Biological Evaluation of 5′-(N-Ethylcarboxamido)adenosine Analogues as Grp94-Selective Inhibitors. Brackett, Young-Hwan Jung, Zhan-Guo Gao, Monimoy Banerjee, Brian S. This article is cited by 42 publications. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. ![]() ![]() While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones.
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