title: ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism.
abstract: The mitotic kinesin KSP (kinesin spindle protein, or Eg5) has an essential role in centrosome separation and formation of the bipolar mitotic spindle. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new anticancer agents with reduced side effects relative to antimitotics that target tubulin. Ispinesib is an allosteric small-molecule KSP inhibitor in phase 2 clinical trials. Mutations that attenuate ispinesib binding to KSP have been identified, which highlights the need for inhibitors that target different binding sites. We describe a new class of selective KSP inhibitors that are active against ispinesib-resistant forms of KSP. These ATP-competitive KSP inhibitors do not bind in the nucleotide binding pocket. Cumulative data from generation of resistant cells, site-directed mutagenesis and photo-affinity labeling suggest that they compete with ATP binding via a novel allosteric mechanism.
authors.affiliation: Department of Enzymology and Mechanistic Pharmacology, Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. lusong.luo@gsk.com
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Parrish
authors.forename: Neysa
authors.initials: N
authors.lastname: Nevins
authors.forename: Dean E
authors.initials: DE
authors.lastname: McNulty
authors.forename: Amita M
authors.initials: AM
authors.lastname: Chaudhari
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Carson
authors.forename: Valery
authors.initials: V
authors.lastname: Sudakin
authors.forename: Antony N
authors.initials: AN
authors.lastname: Shaw
authors.forename: Ruth
authors.initials: R
authors.lastname: Lehr
authors.forename: Huizhen
authors.initials: H
authors.lastname: Zhao
authors.forename: Sharon
authors.initials: S
authors.lastname: Sweitzer
authors.forename: Latesh
authors.initials: L
authors.lastname: Lad
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Wood
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
authors.forename: Roland S
authors.initials: RS
authors.lastname: Annan
authors.forename: Pearl S
authors.initials: PS
authors.lastname: Huang
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jackson
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Auger
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors*; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C097199:KSR-1 protein kinase