Glucose regulated protein (Grp94), the ER isoform of the Hsp90 chaperone family, plays an important role in cellular communication and adhesion. As such, the development of isoform-selective inhibitors will be significant for the elucidation of isoform-dependent biological processes as well as potentially address toxicity issues observed in clinical trials for current Hsp90 inhibitors. To date, however, the development of Hsp90 isoform-selective inhibitors has been limited. Previous work took advantage of a secondary hydrophobic pocket by radamide analogues in which the cis-amide conformation played a critical role for Grp94 inhibition. Therefore, compounds that mimick the cis-amide conformation of radamide could potentially lead to more selective Grp94 inhibitors. Towards this objective, a series of imidazole linked analogues, in which the conformation is locked into a predisposed cis-amide conformation, was synthesized and evaluated for their inhibitory effect on Grp94 and Hsp90. The results from such studies will be presented.

Development of imidazole-based compounds for selective Grp94 inhibition

245th National Meeting (2013)

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