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

Chen Zhang; Peng Tu; Xiangyu Jia; Yuanfeng Xia; Biao Lu; Fanglong Yang; Siqin Wang; Lei Jin

doi:10.1021/acsmedchemlett.4c00383

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

ACS Med Chem Lett. 2024 Sep 17;15(10):1778-1786. doi: 10.1021/acsmedchemlett.4c00383. eCollection 2024 Oct 10.

Authors

Chen Zhang¹, Peng Tu¹, Xiangyu Jia¹, Yuanfeng Xia¹, Biao Lu¹, Fanglong Yang¹, Siqin Wang¹, Lei Jin¹

Affiliation

¹ Changchun Genescience Pharma, 88 Hongmei Road, Xuhui District, Shanghai 200233, China.

PMID: 39411524
PMCID: PMC11472545 (available on 2025-10-10)
DOI: 10.1021/acsmedchemlett.4c00383

Abstract

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.