Triphenylbutanamines: Kinesin Spindle Protein Inhibitors with in Vivo Antitumor Activity

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• 作者：Fang Wang ; James A. D. Good ; Oliver Rath ; Hung Yi Kristal Kaan ; Oliver B. Sutcliffe ; Simon P. Mackay ; Frank Kozielski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 23, 2012
• 年：2012
• 卷：55
• 期：4
• 页码：1511-1525
• 全文大小：543K
• 年卷期：v.55,no.4(February 23, 2012)
• ISSN：1520-4804

文摘

The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit Kb>ib>^app 鈮?10 nM and GIb>50b> 鈮?50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.