TY - JOUR
T1 - Development of a Grp94 inhibitor
AU - Duerfeldt, Adam S.
AU - Peterson, Laura B.
AU - Maynard, Jason C.
AU - Ng, Chun Leung
AU - Eletto, Davide
AU - Ostrovsky, Olga
AU - Shinogle, Heather E.
AU - Moore, David S.
AU - Argon, Yair
AU - Nicchitta, Christopher V.
AU - Blagg, Brian S.J.
PY - 2012/6/13
Y1 - 2012/6/13
N2 - 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.
AB - 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.
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U2 - 10.1021/ja303477g
DO - 10.1021/ja303477g
M3 - Article
C2 - 22642269
AN - SCOPUS:84862157791
SN - 0002-7863
VL - 134
SP - 9796
EP - 9804
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 23
ER -