Abstract
KIF18A is an ATP-dependent, plus end-directed mitotic kinesin that facilitates chromosome alignment and spindle microtubule dynamics during mitosis. Certain cancer types may be particularly vulnerable to KIF18A inhibition, specifically cancer cells with high levels of chromosomal instability (CIN). As part of efforts to identify KIF18A inhibitors, silicon atom replacement was explored to improve ligand-KIF18A interactions and ADME parameters. This tactic resulted in the discovery of a series of silapiperidine-containing KIF18A inhibitors and culminated in the identification and characterization of ATX020. ATX020 is a potent KIF18A inhibitor with a high degree of kinesin selectivity, favorable in vitro and in vivo ADME properties, and robust efficacy in the OVCAR-3 cell-derived xenograft (CDX) model. A high-resolution crystal structure of the KIF18A-tubulin complex and an experimentally guided model of ATX020 bound to the complex are provided, supporting future structure-based drug design of KIF18A inhibitors.