Design, Biological Characterization, and Discovery of Novel Cyclohexenyl Derivatives as Kinesin KIF18A Inhibitors for the Treatment of Ovarian Cancer

A novel class of kinesin KIF18A inhibitors were discovered through modification of the clinical compound AMG650. Structure-activity relationship (SAR) study led to the discovery of compound 16 with an alkenyl motif, a highly potent KIF18A inhibitor, which displayed a favorable pharmacological profile and excellent efficacy in a mouse model of an OVCAR-3 xenograft tumor. Oral administration of 16 can induce a dose-dependent antitumor efficacy in the OVCAR-3 model without significant reduction in body weight. Compound 16 showed potential as a candidate for the clinical treatment of ovarian cancer.