ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism.
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.
Luo
Lusong
L
Department of Enzymology and Mechanistic Pharmacology, Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. lusong.luo@gsk.com
Parrish
Cynthia A
CA
Nevins
Neysa
N
McNulty
Dean E
DE
Chaudhari
Amita M
AM
Carson
Jeffery D
JD
Sudakin
Valery
V
Shaw
Antony N
AN
Lehr
Ruth
R
Zhao
Huizhen
H
Sweitzer
Sharon
S
Lad
Latesh
L
Wood
Kenneth W
KW
Sakowicz
Roman
R
Annan
Roland S
RS
Huang
Pearl S
PS
Jackson
Jeffrey R
JR
Dhanak
Dashyant
D
Copeland
Robert A
RA
Auger
Kurt R
KR
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
D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C097199:KSR-1 protein kinase