High-throughput screening for Hsp90 ATPase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 11; pp. 3005 - 3008
• Main Authors: Avila, Christopher, Hadden, M. Kyle, Ma, Zeqiang, Kornilayev, Boris A., Ye, Qi-Zhuang, Blagg, Brian S.J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-06-2006; Elsevier
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - metabolism; Biological and medical sciences; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; High-throughput screening; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Inhibitors; Medical sciences; Miscellaneous; Molecular Structure; Pharmacology. Drug treatments; Hsp90; High-throughput screening; Inhibitors; High throughput screening; Yeast; Enzyme; Chaperone; Adenosinetriphosphatase; Enzyme inhibitor; Biological activity; Signal transduction; Heat shock protein; Test method; Hydrolases; Large scale
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.02.063

Recently, we reported a useful assay for the determination of Hsp90 ATPase activity. Using this assay, high-throughput screening of ∼10,000 compounds was performed to determine the feasibility of this assay on large scale. Results from high-throughput screening indicated that the assay was reproducible (av
Z-factor
=
0.80) and identified 0.57% of the compounds as Hsp90 inhibitors that exhibited IC
50s less than 20
μM. The structures of several of these inhibitory scaffolds are reported along with their IC
50 values.
Recently, we reported a useful assay for the determination of yeast Hsp90 ATPase activity. Using this assay, high-throughput screening of ∼10,000 compounds was performed to determine the feasibility of this assay on large scale. Results from high-throughput screening indicated that the assay was reproducible (av
Z-factor
=
0.80) and identified 0.57% of the compounds as Hsp90 inhibitors that exhibited IC
50s less than 20
μM. The structures of several of these inhibitory scaffolds are reported along with their IC
50 values.