title: Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP.
abstract: Optimization of high-throughput screening (HTS) hits resulted in the discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of KSP. Dihydropyrazole 15 is a potent, cell-active KSP inhibitor that induces apoptosis and generates aberrant mitotic spindles in human ovarian carcinoma cells at low nanomolar concentrations. X-ray crystallographic evidence is presented which demonstrates that these inhibitors bind in an allosteric pocket of KSP distant from the nucleotide and microtubule binding sites.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. chris_cox@merck.com <chris_cox@merck.com>
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Mariano
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D011720:Pyrazoles; D016547:Kinesins