Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

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• 作者：Naohisa Ogo ; Yoshinobu Ishikawa ; Jun-ichi Sawada ; Kenji Matsuno ; Akihiro Hashimoto ; Akira Asai
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：6
• 期：9
• 页码：1004-1009
• 全文大小：311K
• ISSN：1948-5875

文摘

Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle. We previously reported S-trityl-l-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo.