Duerfeldt, A.S., Peterson, L.B., Maynard, J.C., Ng, C.L., Eletto, D., Ostrovsky, O., Shinogle, H.E., Moore, D.S., Argon, Y., Nicchitta, C.V., Blagg, B.S. (2012). Development of a Grp94 inhibitor.  J. Am. Chem. Soc. 134(23): 9796--9804.

FBrf0218573

Research paper

Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90α/β (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90α/β client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.

PMC3414055 (PMC) (EuropePMC)