Novel ATP-Competitive Kinesin Spindle Protein Inhibitors

详细信息    查看全文

• 作者：Cynthia A. Parrish ; Nicholas D. Adams ; Kurt R. Auger ; Joelle L. Burgess ; Jeffrey D. Carson ; Amita M. Chaudhari ; Robert A. Copeland ; Melody A. Diamond ; Carla A. Donatelli ; Kevin J. Duffy ; Leo F. Faucet
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4939 - 4952
• 全文大小：250K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that ispresent only in proliferating cells, has become a novel and attractive anticancer target with potential forreduced side effects compared to currently available therapies. We report herein the discovery of the firstknown ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the knownloop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this seriesled to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferativeactivity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In amurine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity followingintraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSPinhibitor versus tumors that are resistant to the other known KSP inhibitors.