Abstract Title
Preclinical profile of novel and potent small molecule inhibitors of KIF18A in chromosomally unstable solid tumor lines
Abstract
Background: Accurate alignment of chromosomes at the metaphase plate and equal chromosome segregation during cell division are essential for genome integrity. KIF18A, a kinesin superfamily microtubule motor protein, maintains bipolar spindle integrity during mitosis. Chromosomally unstable (CIN+) cancer cells show synthetic lethality with KIF18A ablation, making its pharmacological inhibition a promising strategy for CIN+ tumors.
Methods: Potent KIF18A inhibitors were identified using a microtubule-dependent ADP-Glo kinase assay. Mitotic arrest was assessed via phospho-H3 staining and fluorescence microscopy. Anti-proliferative activity was evaluated in CIN+ solid tumor cells with parallel assessment in CIN- controls. Selectivity was determined by comparing effects in OVCAR-3 (CIN+) versus HCT-116 (CIN-) cells.
Results: Compounds inhibited KIF18A with potencies of 50-80 nM. Dose-dependent mitotic index increases (10-100× selective for CIN+ cells) and antiproliferative activity (IC50 <10 nM in CIN+ cells) were observed. Lead molecules demonstrated favorable physicochemical properties, ADME profiles, and pharmacokinetics. The synthetic lethal phenotype was confirmed by selective activity in CIN+ models.
Conclusion: These novel KIF18A inhibitors show potent, selective activity against chromosomally unstable tumors, supporting their development as targeted therapies for CIN+ cancers. In vivo efficacy studies are planned to further characterize these promising compounds.
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