A high throughput, whole cell screen for small molecule inhibitors of the mitotic spindle checkpoint identifies OM137, a novel Aurora kinase inhibitor.
In mitosis, the kinetochores of chromosomes that lack full microtubule attachments and/or mechanical tension activate a signaling pathway called the mitotic spindle checkpoint that blocks progression into anaphase and prevents premature segregation of the chromatids until chromosomes become aligned at the metaphase plate. The spindle checkpoint is responsible for arresting cells in mitosis in response to chemotherapeutic spindle poisons such as paclitaxel or vinblastine. Some cancer cells show a weakened checkpoint signaling system that may contribute to chromosome instability in tumors. Because complete absence of the spindle checkpoint leads to catastrophic cell division, we reasoned that drugs targeting the checkpoint might provide a therapeutic window in which the checkpoint would be eliminated in cancer cells but sufficiently preserved in normal cells. We developed an assay to identify lead compounds that inhibit the spindle checkpoint. Most cells respond to microtubule drugs by activating the spindle checkpoint and arresting in mitosis with a rounded morphology. Our assay depended on the ability of checkpoint inhibitor compounds to drive mitotic exit and cause cells to flatten onto the substrate in the continuous presence of microtubule drugs. In this study, we characterize one of the compounds, OM137, as an inhibitor of Aurora kinases. We find that this compound is growth inhibitory to cultured cells when applied at high concentration and potentiates the growth inhibitory effects of subnanomolar concentrations of paclitaxel.
DeMoe
Joanna H
JH
Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Santaguida
Stefano
S
Daum
John R
JR
Musacchio
Andrea
A
Gorbsky
Gary J
GJ
D064127:Aurora Kinases; D002455:Cell Division / Q000187:drug effects; D043171:Chromosomal Instability; D002877:Chromosomes, Human / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D008941:Spindle Apparatus / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006835:Hydrazones; C539245:OM 137; D013844:Thiazoles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D015739:Nocodazole