2. Academic Validation
  3. Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

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

  • ACS Med Chem Lett. 2015 Jul 22;6(9):1004-9. doi: 10.1021/acsmedchemlett.5b00221.
Naohisa Ogo 1,  Yoshinobu Ishikawa 2,  Jun-Ichi Sawada 1,  Kenji Matsuno 1,  Akihiro Hashimoto 3,  Akira Asai 1
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka , Shizuoka 422-8526, Japan.
  • 2 Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka , Shizuoka 422-8526, Japan.
  • 3 Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd. , 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.
PMID: 26396688 DOI: 10.1021/acsmedchemlett.5b00221
Abstract

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.

Keywords

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

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