Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe

Chromosomal
instability (CIN) is a hallmark of cancer that results
from errors in chromosome segregation during mitosis. Targeting of
CIN-associated vulnerabilities is an emerging therapeutic strategy
in drug development. KIF18A, a mitotic kinesin, has been shown to
play a role in maintaining bipolar spindle integrity and promotes
viability of CIN cancer cells. To explore the potential of KIF18A,
a series of inhibitors was identified. Optimization of an initial
hit led to the discovery of analogues that could be used as chemical
probes to interrogate the role of KIF18A inhibition. Compounds 23 and 24 caused significant mitotic arrest in
vivo, which was sustained for 24 h. This would be followed by cell
death either in mitosis or in the subsequent interphase. Furthermore,
photoaffinity labeling experiments reveal that this series of inhibitors
binds at the interface of KIF18A and tubulin. This study represents
the first disclosure of KIF18A inhibitors with in vivo activity.