Abstract LB188: YF550 is a potent and selective inhibitor of KIF18A, specifically targeting CIN+ cancer cells

Abstract Chromosomal instability (CIN+) characterizes a continuous mitotic dysfunction leading to karyotypic abnormalities and aneuploidy, commonly observed in various human cancers, including ovarian, triple-negative breast (TNBC), and head-and-neck tumors, with significant implications for tumor progression and prognosis. KIF18A, a mitotic kinesin motor protein essential for chromosome alignment during cell division, is critical for the proliferation of CIN+ cells but dispensable in near-diploid cells. Inhibition of KIF18A results in mitotic delays, multipolar spindle formation, and elevated cell death in CIN+ tumor cells. YF550 is a highly selective and potent inhibitor in KIF18A inhibitor and CIN+ cellular proliferation assays, as well as in phospho-Histone H3 mitotic marker evaluation. YF550 exhibits exceptional selectivity for KIF18A over related protein Eg5 and several other proteins. In contrast to the Eg5 inhibitor Ispinesib, YF550 does not inhibit normal PBMC proliferation. Notably, the cellular potency of YF550 correlates with the aneuploidy score of CIN+ cancer cells, which may serve as a potential biomarker for patient stratification. YF550 has demonstrated synergistic effects when combined with various agents, including Olaparib (PARP inhibitor), PF-07104091 (CDK2 inhibitor), Elimusertib (ATR inhibitor), Volasertib (PLK1 inhibitor), and MMAE, in cellular proliferation assays. In the OVCAR3 ovarian cancer xenograft model, YF550 has shown superior efficacy compared to KIF18A inhibitor AMG650 at a 5 mg/kg dose, with no significant impact on body weight. Furthermore, YF550 induced tumor regression in both the OVCAR8 ovarian and JIMT-1 HER2 positive breast cancer xenograft models. YF550 exhibits superior ADME and PK property suitable for clinical development for CIN+ cancers with high aneuploidy score and has the potential for combination therapy with PD-1/L1 antibodies, PARP1 inhibitors, and MMAE based ADC. Citation Format: Yaolin Wang, Rongfeng Liu, Hong Yang, Yong Luo, Younong Yu, Jifang Weng, Yan Weng, Hong Mei, David Dai. YF550 is a potent and selective inhibitor of KIF18A, specifically targeting CIN+ cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB188.