Discovery of Aminoquinolines as a New Class of Potent Inhibitors of Heat Shock Protein 90 (Hsp90): Synthesis, Biology and Molecular Modeling

• Type of Material: Article
• Authors: Thota Ganesh, Emory University; Jaeki Min, Emory University; Pahk Thepchatri, Emory University; Yuhong Du, Emory University; Lian Li, Emory University; Iestyn Lewis, Emory University; Larry Wilson, Emory University; Haian Fu, Emory University; Gabriela Chiosis, Memorial Sloan-Kettering Cancer Center; Raymond J Dingledine, Emory University; Dennis C Liotta, Emory University; James P Snyder, Emory University; Aiming Sun, Emory University
• Language: English
• Date: 2008-07-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier Ltd.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016%2Fj.bmc.2008.05.047
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry
• ISSN: 0968-0896
• Volume: 16
• Issue: 14
• Start Page: 6903
• End Page: 6910
• Grant/Funding Information: This work was financially supported by the US National Institutes of Health 1 U54 HG003918-02 and 1R03MH076499-01.
• Keywords: high-throughput screening (HTS); Heat Shock Protein 90 (Hsp90); aminoquinoline
• Research Categories: Chemistry, Biochemistry; Biology, Molecular; Health Sciences, Pharmacology

Abstract

The molecular chaperone Hsp90 plays important roles in maintaining the 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 been 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.