Development of a Grp94 inhibitor.
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.
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
Adam S
AS
Duerfeldt
Laura B
LB
Peterson
Jason C
JC
Maynard
Chun Leung
CL
Ng
Davide
D
Eletto
Olga
O
Ostrovsky
Heather E
HE
Shinogle
David S
DS
Moore
Yair
Y
Argon
Christopher V
CV
Nicchitta
Brian S J
BS
Blagg
D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000187:drug effects / Q000254:growth & development; D015195:Drug Design; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins; D051193:Toll-Like Receptors; C018551:glucose-regulated proteins; D007335:Insulin-Like Growth Factor II