title: Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP.
abstract: The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition. In a high-throughput screen for inhibitors of KSP, a novel class of thiazole-containing inhibitors was identified. Unlike the previously described allosteric KSP inhibitors, the thiazoles described here show ATP competitive kinetic behavior, consistent with binding within the nucleotide binding pocket. Although they bind to a pocket that is highly conserved across kinesins, these molecules exhibit significant selectivity for KSP over other kinesins and other ATP-utilizing enzymes. Several of these compounds are active in cells and produce a phenotype similar to that observed with previously published allosteric inhibitors of KSP.
authors.affiliation: Department of Cancer Research, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA. keith_rickert@merck.com
authors.forename: Keith W
authors.initials: KW
authors.lastname: Rickert
authors.forename: Michael
authors.initials: M
authors.lastname: Schaber
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: Lou Anne
authors.initials: LA
authors.lastname: Neilson
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tasber
authors.forename: Robert
authors.initials: R
authors.lastname: Garbaccio
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Diane
authors.initials: D
authors.lastname: Harvey
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Gary
authors.initials: G
authors.lastname: Marshall
authors.forename: Ling
authors.initials: L
authors.lastname: Lee
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000495:Allosteric Site; D001667:Binding, Competitive; D001671:Biochemistry / Q000379:methods*; D015195:Drug Design; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008938:Mitosis; D008954:Models, Biological; D008956:Models, Chemical; D009711:Nucleotides / Q000737:chemistry; D010641:Phenotype; D011485:Protein Binding; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C470243:KIF11 protein, human; D009711:Nucleotides; D013844:Thiazoles; D000255:Adenosine Triphosphate; D016547:Kinesins