Mad2 Inhibitor-1 (M2I-1): A Small Molecule Protein鈥揚rotein Interaction Inhibitor Targeting the Mitotic Spindle Assembly Checkpoint

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• 作者：Johanna Kastl ; Joachim Braun ; Andreas Prestel ; Heiko M. M枚ller ; Thomas Huhn ; Thomas U. Mayer
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：July 17, 2015
• 年：2015
• 卷：10
• 期：7
• 页码：1661-1666
• 全文大小：339K
• ISSN：1554-8937

文摘

The genetic integrity of each organism depends on the faithful segregation of its genome during mitosis. To meet this challenge, a cellular surveillance mechanism, termed the spindle assembly checkpoint (SAC), evolved that monitors the correct attachment of chromosomes and blocks progression through mitosis if corrections are needed. While the central role of the SAC for genome integrity is well established, its functional dissection has been hampered by the limited availability of appropriate small molecule inhibitors. Using a fluorescence polarization-based screen, we identify Mad2 inhibitor-1 (M2I-1), the first small molecule inhibitor targeting the binding of Mad2 to Cdc20, an essential protein鈥損rotein interaction (PPI) within the SAC. Based on computational and biochemical analyses, we propose that M2I-1 disturbs conformational dynamics of Mad2 critical for complex formation with Cdc20. Cellular studies revealed that M2I-1 weakens the SAC response, indicating that the compound might be active in cells. Thus, our study identifies the SAC specific complex formation between Mad2 and Cdc20 as a protein鈥損rotein interaction that can be targeted by small molecules.