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Abstract KIF18A belongs to the kinesin-8 subfamily and is a plus-end-directed motor, which regulates kinetochore microtubules dynamics to control mitotic chromosome alignment and spindle tension. Studies have shown that genetic depletion or pharmacological inhibition of KIF18A is a promising therapeutic approach for cancers, exhibiting high chromosomal instability (CIN-high), without having a significant impact on the normal division of euploid cells. Here, we report the discovery and preclinical evaluation of ISM9682A, a novel KIF18A inhibitor with excellent potency and high selectivity. ISM9682A is a potent KIF18A inhibitor with a single-digit nanomolar IC50 value and exhibits high selectivity over other kinesin family members. In addition, ISM9682A demonstrated excellent monotherapy anti-proliferative activity, with single-digit nanomolar IC50 values, in high-grade serous ovarian carcinoma (HGSOC) as well as in triple-negative breast cancer (TNBC) aneuploid cell lines with p53 mutation. Notably, ISM9682A exhibited a prolonged drug-target residence time indicated by both enzymatic and cellular assays. Consistent with the in vitro findings, ISM9682A displayed significant anti-tumor efficacy with a robust pharmacodynamic response (pH3, mitotic marker; γH2AX, DNA damage marker) in OVCAR3 and HCC1806 CDX models in a dose-dependent manner. In addition to its robust biological potency and high selectivity, ISM9682A exhibits favorable drug-like properties, including desirable in vitro ADMET characteristics and excellent in vivo exposure, clearance, as well as good oral bioavailability across multiple preclinical species. Collectively, these findings highlight the potential of ISM9682A as a novel and highly potent KIF18A inhibitor for the treatment of CIN-high cancers. Citation Format: Jie Zhang, Feng Gao, Wei Zhu, Chenxi Xu, Xiaoyu Ding, Jing Shang, Junwen Qiao, Shan Chen, Xin Cai, Xiao Ding, Supriya Bavadekar, Sujata Rao, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM9682A, a novel and potent KIF18A inhibitor, shows robust antitumor effects against chromosomally unstable cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5727.
Zhang et al. (Fri,) studied this question.