High-Throughput Screening System To Identify Small Molecules That Induce Internalization and Degradation of HER2

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• 作者：Masayuki Isa ; Daisuke Asanuma ; Shigeyuki Namiki ; Kazuo Kumagai ; Hirotatsu Kojima ; Takayoshi Okabe ; Tetsuo Nagano ; Kenzo Hirose
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：October 17, 2014
• 年：2014
• 卷：9
• 期：10
• 页码：2237-2241
• 全文大小：277K
• ISSN：1554-8937

文摘

Overexpression of growth factor receptors in cancers, e.g., human epidermal growth factor receptor 2 (HER2) in ovarian and breast cancers, is associated with aggressiveness. A possible strategy to treat cancers that overexpress those receptors is blockade of receptor signaling by inducing receptor internalization and degradation. In this study, we developed a cell-based high-throughput screening (HTS) system to identify small molecules that induce HER2 internalization by employing our recently developed acidic-pH-activatable probe in combination with protein labeling technology. Our HTS system enabled facile and reliable quantification of HER2 internalization with a Z鈥?factor of 0.66 and a signal-to-noise ratio of 44.6. As proof of concept, we used the system to screen a 鈭?55,000 small-molecule library and identified three hits that induced HER2 internalization and degradation via at least two distinct mechanisms. This HTS platform should be adaptable to other disease-related receptors in addition to HER2.