Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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

Authors:	Naohisa Ogo Yoshinobu Ishikawa Jun-ichi Sawada Kenji Matsuno Akihiro Hashimoto Akira Asai

Affiliation:	^†Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan;^‡Department of Physical Biochemistry, School of Pharmaceutical Sciences, University ofShizuoka, Shizuoka 422-8526, Japan;^§Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan

Abstract:	l-cysteine derivatives as selective KSP inhibitors. Here, wereport further optimizations using docking modeling in the L5 allostericbinding site, which led to the discovery of several high affinityderivatives with two fused phenyl rings in the trityl group givinglow nanomolar range KSP ATPase inhibition. The representative derivativespotently inhibited cell growth of HCT116 cells in correlation withKSP inhibitory activities and significantly suppressed tumor growthin the xenograft model in vivo.

Keywords:	Kinesin spindle protein l-cysteine derivative molecular modeling differential scanning fluorimetry HCT-116 xenograftmodel