BTB-1

The survival and development of each organism relies on the equal partitioning of its genome during cell division.Key for the accurate distribution of the genome is the mitotic spindle composed of dynamic microtubules.Recently, we identified the kinesin-8 member Kif18A as a central component for the correct alignment of chromosomes at the spindle equator.We report herein the discovery of the first inhibitor of Kif18A, BTB-1, identified by a protein-based, reverse-chem. genetic screen.Our chem.-biol.-based approach has provided access to a new tool for studying a protein key for chromosome segregation in mammalian cells.

Chromosomal instability (CIN), a hallmark of over 90% of solid tumors, presents both a vulnerability and an opportunity in cancer therapy. KIF18A, a kinesin motor protein essential for mitotic fidelity, becomes critical for CIN cancer cells, where it suppresses lethal mitotic errors. This selective dependency makes KIF18A an attractive therapeutic target.

This review explores the structural and functional biology of KIF18A, its role in maintaining chromosomal alignment, and how its inhibition leads to mitotic failure specifically in cancer cells exhibiting high CIN. We summarize the development of small-molecule inhibitors, from early compounds like BTB-1 to second-generation agents including Sovilnesib and VLS-1488, the latter currently in Phase I/II trials. Clinical data show manageable toxicity and promising antitumor activity, particularly in high-grade serous ovarian cancer. New entrants like ATX-295 and GH2616 further expand the landscape. We also highlight efforts to refine KIF18A targeting through structural studies and emerging AI-driven drug discovery.

KIF18A inhibition represents a mechanistically grounded, tumor-selective strategy for treating CIN-driven cancers. As clinical trials progress, optimizing patient stratification and exploring synergistic combinations will be crucial. Broadening the range of druggable sites on KIF18A, especially beyond the motor domain, could mitigate resistance and help expand therapeutic potential.