@article{82bc4ed4f8424d04ab4ddea1608f68b0,
title = "Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes",
abstract = "The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro. We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.",
author = "Dumas, {Megan E.} and Chen, {Geng Yuan} and Kendrick, {Nicole D.} and George Xu and Larsen, {Scott D.} and Somnath Jana and Waterson, {Alex G.} and Bauer, {Joshua A.} and William Hancock and Sulikowski, {Gary A.} and Ryoma Ohi",
note = "Funding Information: We thank members of the R. Ohi, M. Zanic and M. Lang labs for insightful discussions and Bryan Tsou (Memorial Sloan Ketterling Cancer Center) for the RPE-1 TP53-/- cell line. We acknowledge the Vanderbilt Institute of Chemical Biology chemical synthesis core and the Vanderbilt High Throughput Screening facility for technical support and useful discussions. This work was supported by National Institutes of Health grants R01GM086610 to R. Ohi and R50 CA211206 to J.B. R. Ohi was also supported by a Scholar Career Development Award from the Leukemia and Lymphoma Society. We thank GlaxoSmithKline LCC for providing the kinase inhibitor library PKIS, https://www.sgc-unc.org/kinase-chemogenomics/. Funding Information: We thank members of the R. Ohi, M. Zanic and M. Lang labs for insightful discussions and Bryan Tsou (Memorial Sloan Ketterling Cancer Center) for the RPE-1 TP53 -/- cell line. We acknowledge the Vanderbilt Institute of Chemical Biology chemical synthesis core and the Vanderbilt High Throughput Screening facility for technical support and useful discussions. This work was supported by National Institutes of Health grants R01GM086610 to R. Ohi and R50 CA211206 to J.B. R. Ohi was also supported by a Scholar Career Development Award from the Leukemia and Lymphoma Society . We thank GlaxoSmithKline LCC for providing the kinase inhibitor library PKIS, https://www.sgc-unc.org/kinase-chemogenomics/ . Publisher Copyright: {\textcopyright} 2018",
year = "2019",
month = jan,
day = "15",
doi = "10.1016/j.bmcl.2018.12.008",
language = "English (US)",
volume = "29",
pages = "148--154",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "2",
}
