Abstract 5637: A novel KIF18A inhibitor for targeting chromosomal instability in cancer

Abstract Anti-mitotic drugs are frequently used to treat cancer and many work by targeting microtubules and disrupting the mitotic phase of the cell cycle. However, dose-limiting toxicity associated with inhibition of cell division in normal cells limits the clinical benefit of this drug class. The spindle assembly checkpoint (SAC) has emerged as a vulnerability for cancer cells with chromosomal instability due to their increased dependence on proper chromosome alignment. KIF18A is a kinesin family motor protein that promotes chromosome alignment by dampening chromosome oscillation. Targeting KIF18A provides an opportunity for cancer-specific dysregulation of the SAC and therefore a significantly improved therapeutic window. Here we describe a novel series of potent KIF18A inhibitors (IC50 < 30 nM) in both KIF18A ATPase biochemical and OVCAR-3 cell growth inhibition assays. These KIF18A inhibitors demonstrated >300-fold selectivity against other kinesins that are essential for various cellular functions. The high selectivity of these inhibitors is reflected in the lack of in vitro toxicity in normal dividing cells and bone marrow hematopoietic progenitor cells. Furthermore, the anti-proliferative activity is highly correlated with biochemical activity, with increased levels of the mitotic phase biomarker pHH3, and with increased arrest of cells in the mitotic phase. Utilizing the predictive power of Iambic’s AI-driven platform, compounds in this series were optimized to exhibit a favorable ADME profile, low risk of drug-drug interaction liabilities and good bioavailability across multiple rodent and non-rodent preclinical species. The lead molecule IAM-K1 in this series is negative in the mini Ames genotoxicity test and has favorable predicted human pharmacokinetics and metabolism. IAM-K1 displays >10 uM direct IC50 inhibition against the major human cytochrome P450 enzymes, including 2C9, 2C19 and 3A4, reducing the risk to alter the metabolism of co-administered drugs. IAM-K1 has robust anti-proliferation activity in a number of cell lines, representing different cancer indications, and is approximately 2-3 fold more potent than a reference compound AMG650. Furthermore, IAM-K1 achieves similar PD and TGI efficacy as AMG650 in vivo at much lower systemic exposure. Repeat oral dosing of IAM-K1 led to durable tumor regression in the OVCAR-3 xenograft mouse model without impacting body weight. The anti-tumor activity is correlated with an increase in pHH3 in xenograft tumors, consistent with the on-target mechanism of mitotic arrest. Together with a predictive biomarker approach, targeting KIF18A with IAM-K1 and other compounds in this series is expected to provide a novel anti-cancer treatment to patients with a wide therapeutic window. Citation Format: Lana Kulyk, Shawn Wright, Jill Hallin, Michael Maestre, Joseph Dennis, Iriny Botrous, Anders S. Christensen, Jan Pencik, Craig Gutierrez, Afsheen Banisadr, Jeeyoung Park, Abby Adams, Chang Zhao, Kelly Chen, Stephen Munoz, Shane Yost, Marcelo Lacerda, Angus Voice, Mary L. Anderson, Bo Liu, Matt Welborn, Chao Zhang, Jeff Hager, Fred Manby, Tom Miller, Hui Zhang, Laurent Gomez, Peter Olson, Zhongdong Huang, Chunmei Zhao. A novel KIF18A inhibitor for targeting chromosomal instability in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5637.