Small molecule screen to identify mitotic kinesin KIF18A inhibitors
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Mitotic cell division is critically reliant on consistent and faithful segregation of genetic information into newly forming daughter cells. Any perturbation in this process can have catastrophic intracellular effects and as such, many natural mechanisms occur during mitosis to prevent these anomalous events. Kinesins make up 14 families of motor proteins, using ATP-driven movement along microtubules to fulfill a range of functions, including organelle and vesicular transport. One such kinesin, plus-end directed KIF18A of the Kinesin 8 family, has been extensively investigated and found to be critically associated with restricting chromosome oscillation during chromosome alignment at the metaphase plate. Depletion of KIF18A subtly increases mitotic duration, chromosome oscillations, lagging chromosomes, and micronucleus formation in normal diploid cells and has minimal effects on cell viability. By contrast, loss of Kif18A induces severe mitotic defects that significantly impair viability in whole genome-doubled and highly aneuploid cells. As tetraploidization or whole genome doubling has been linked to large percentages of cancer types, this dependence on KIF18A has been proposed as a possible therapeutic target for cancer treatment. Two known KIF18A inhibitors exist; however, their function is either limited (BTB-1) or the efficacy remains to be publicly validated (Amgen). In this thesis, a screening protocol involving fluorescent-based live cell imaging was formulated to test several small molecule compounds that were suspected to have compatibilities with a binding site on KIF18A. Through the screening process, Compound 3 was identified and found to demonstrate a phenotype similar to KIF18A depletion—prolonged mitosis, decreased cell proliferation/viability, and induction of chromosome oscillation. Further examination of this compound as a potential therapeutic and elucidation of its specific mechanism of action appear to be warranted for future studies.
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