Identification of the KIF18A alpha-4 helix as a therapeutic target for chromosomally unstable tumor cells

• DOI: 10.3389/fmolb.2024.1328077
• Publication Date: 2024-02-12T15:39:02Z
• Authors: Katherine L. Schutt; Katelyn A. Queen; Kira Fisher; Olivia Budington; Weifeng Mao; Wei Liu; Xiaohui Gu; Yisong Xiao; Fred Aswad; James Joseph; Jason Stumpff
• Keywords: mitosis; 0303 health sciences; KIF18A; QH301-705.5; spindle; Biochemistry, Genetics and Molecular Biology (miscellaneous); Biochemistry; kinesin; 03 medical and health sciences; Molecular Biosciences; Biology (General); chromosome instability; Molecular Biology; small-molecule inhibitor

Background: The mitotic kinesin, KIF18A, is required for proliferation of cancer cells that exhibit chromosome instability (CIN), implicating it as a promising target treatment subset aggressive tumor types. Determining regions the KIF18A protein to inhibition will be important design and optimization effective small molecule inhibitors. Methods: In this study, we used cultured cell models investigate effects mutating S284 within alpha-4 helix which was previously identified phosphorylated residue. Results: Mutations in cause relocalization from plus-ends spindle microtubules poles. Furthermore, mutants display loss function fail support CIN cells. Interestingly, similar on localization were seen after with inhibitory compounds are predicted interact residues helix. Conclusion: These data implicate an demonstrate molecules targeting selectively limit result phenotypically mitosis at single level compared genetic perturbations.