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Abstract Chromosome instability (CIN) and Genetic instability is a common feature of malignant tumor cells, which may contribute to tumor progression and lead to drug resistance and tumor metastasis. KIF18A, a member of the kinesin-8 family, is an ATP dependent plus end microtubule motor protein. Studies have found that genetic depletion of KIF18A greatly impacts the chromosome alignment, elongation of mitotic spindles, activation spindle assembly checkpoint of CIN+ tumor cell and leads to cell death, while have little impact towards the survival of normal cells, making KIF18A an attractive therapeutic target for targeting the vulnerability of CIN related tumors. Here we report the pharmacology characterization of a “best in class” potential KIF18A inhibitor for CIN+ tumors. In vitro, GSC000190 inhibited KIF18A ATPase activity with a single nM potency and has great potency inhibiting growth of a wide range of TP53 mutant/CIN+ tumor cells. In vivo, GSC000190, at approximately one tenth of systematic exposure comparing to that of AMG650, the leading clinical KIF18A inhibitor, causes tumor shrinkage in multiple CDX models including ovarian, colon and lung cancers. In an HGSOC PDX model which is resistant to platinum and olaparib, GSC000190 induced strong tumor regression both as single agent and through combination without significant body weight reduction. PD study confirms a more elevated mitotic phosphorylated histone 3 (PH3) staining in GSC000190 treated tumor tissues, correlating with a better in vivo efficacy than that of AMG650. GSC000190 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GSC000190 is now under IND-enabling study and P1 study is planned in the second quarter of 2024. Legal entity responsible for the study: The authors. Disclosure: All authors have declared no conflicts of interest. Citation Format: Peng Tu, Chen Zhang, Biao Lu, Yuanfeng Xia, Fanglong Yang. GSC000190, a highly potent inhibitor of KIF18A, for tumors with chromosome instability 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 664.
Tu et al. (Fri,) studied this question.