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.
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.
Cox
Christopher D
CD
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>
Breslin
Michael J
MJ
Mariano
Brenda J
BJ
Coleman
Paul J
PJ
Buser
Carolyn A
CA
Walsh
Eileen S
ES
Hamilton
Kelly
K
Huber
Hans E
HE
Kohl
Nancy E
NE
Torrent
Maricel
M
Yan
Youwei
Y
Kuo
Laurence C
LC
Hartman
George D
GD
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
D018797:Cell Cycle Proteins; D011720:Pyrazoles; D016547:Kinesins