2. Academic Validation
  3. Novel ATP-competitive kinesin spindle protein inhibitors

Novel ATP-competitive kinesin spindle protein inhibitors

  • J Med Chem. 2007 Oct 4;50(20):4939-52. doi: 10.1021/jm070435y.
Cynthia A Parrish 1,  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 Faucette,  Jeffrey T Finer,  William F Huffman,  Erin D Hugger,  Jeffrey R Jackson,  Steven D Knight,  Lusong Luo,  Michael L Moore,  Ken A Newlander,  Lance H Ridgers,  Roman Sakowicz,  Antony N Shaw,  Chiu-Mei M Sung,  David Sutton,  Kenneth W Wood,  Shu-Yun Zhang,  Michael N Zimmerman,  Dashyant Dhanak
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Oncology Center of Excellence for Drug Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. [email protected]
PMID: 17725339 DOI: 10.1021/jm070435y
Abstract

Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during Mitosis that is present only in proliferating cells, has become a novel and attractive Anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the Other known KSP inhibitors.

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