Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein 90 (Hsp90): Synthesis, biology, and molecular modeling.
The molecular chaperone Hsp90 plays important roles in maintaining malignant phenotypes. Recent studies suggest that Hsp90 exerts high-affinity interactions with multiple oncoproteins, which are essential for the growth of tumor cells. As a result, research has focused on finding Hsp90 probes as potential and selective anticancer agents. In a high-throughput screening exercise, we identified quinoline 7 as a moderate inhibitor of Hsp90. Further hit identification, SAR studies, and biological investigation revealed several synthetic analogs in this series with micromolar activities in both fluorescent polarization (FP) assay and a cell-based Western blot (WB) assay. These compounds represent a new class of Hsp90 inhibitors with simple chemical structures.
Chemical Biology Discovery Center, 1510 Clifton Road, Emory University, Atlanta, GA 30322, USA.
Thota
T
Ganesh
Jaeki
J
Min
Pahk
P
Thepchatri
Yuhong
Y
Du
Lian
L
Li
Iestyn
I
Lewis
Larry
L
Wilson
Haian
H
Fu
Gabriela
G
Chiosis
Raymond
R
Dingledine
Dennis
D
Liotta
James P
JP
Snyder
Aiming
A
Sun
D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents; D015153:Blotting, Western; D004353:Drug Evaluation, Preclinical; D016231:Fluorescence Polarization Immunoassay; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins