Discovery of Novel Allosteric Eg5 Inhibitors Through Structure-Based Virtual Screening

详细信息    查看全文

• 作者：Wei Zhang ; Ling Zhai ; Wenyan Lu ; Rebecca J. Boohaker ; Indira Padmalayam and Yonghe Li
• 刊名：Chemical Biology & Drug Design
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：88
• 期：2
• 页码：178-187
• 全文大小：1176K
• ISSN：1747-0285

文摘

Mitotic kinesin Eg5 is an attractive anticancer drug target. Discovery of Eg5 inhibitors has been focused on targeting the ‘monastrol-binding site’. However, acquired drug resistance has been reported for such inhibitors. Therefore, identifying new Eg5 inhibitors which function through a different mechanism(s) could complement current drug candidates and improve drug efficacy. In this study, we explored a novel allosteric site of Eg5 and identified new Eg5 inhibitors through structure-based virtual screening. Experiments with the saturation-transfer difference NMR demonstrated that the identified Eg5 inhibitor SRI35566 binds directly to Eg5 without involving microtubules. Moreover, SRI35566 and its two analogs significantly induced monopolar spindle formation in colorectal cancer HCT116 cells and suppressed cancer cell viability and colony formation. Together, our findings reveal a new allosteric regulation mechanism of Eg5 and a novel drug targeting site for cancer therapy.