The development of isoform-selective Hsp-90 inhibitors provides an opportunity to reduce the side effects that results from pan-inhibition of all four human isoforms:  Hsp90a, Hsp90�, Grp94, TRAP-1. To date, several client Grp94 client proteins have been identified which involve the Toll-like receptors, integrins, IGF-I, IGF-II, and immunoglobulins. In addition, inhibition of Grp94 has been implicated for the treatment of various diseases, including arthritis, glaucoma, and multiple myeloma. Recently, Grp94 co-crystal structures were solved and shown to contain a secondary binding site that provides an opportunity to develop isoform-selective inhibitors. These crystal structures were used as a platform to develop Grp94 selective inhibitors. Results suggest that rational drug design can lead to the development of isoform-selective compounds for inhibition of closely related Hsp90 isoforms. In this work, Grp94 inhibitors were designed using the resorcinol ring of natural product radicicol as a starting point. Synthesis and biological evaluation of these Grp94-selctive inhibitors will be presented herein.

Development of selective Grp94 inhibitors derived from radicicol

248th National Meeting (2014)

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