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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

Institution:	^†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 of Shizuoka, 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, 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.

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