Abstract 5946: ZM-412, a potent and selective KIF18A inhibitor with robust efficacy as monotherapy in CIN-positive tumors and in combination with MMAE-conjugated ADC in CIN-negative tumors

Abstract Chromosomal instability (CIN), a hallmark of human cancer, is defined as the perpetual missegregation of whole chromosomes during mitosis. KIF18A has emerged as a potential therapeutic target of synthetic lethality to induce CIN tumor cell death because it is more required for the proliferation of CIN tumor cells than normal diploidy cells. Here, we identified a potent and selective KIF18A inhibitor ZM-412. In vitro, ZM-412 inhibited the kinesin motor enzymatic activity with an IC50 less than 30 nM, and arrested OVCAR3 cells in the G2/M phase with an EC50 around 2.0 nM. ZM-412 also selectively inhibited the proliferation of a panel of CIN-positive tumor cell lines with IC50 values less than 50 nM, whereas it didn’t affect the proliferation of CIN-negative cells such as PBMC and near-diploidy HCT116 as indicated by IC50 values over than 5 μM. A CIN-positive HCT116CIN model was established by cytochalasin D induction. Compared to parent HCT116 cells, it was sensitive to ZM-412 treatment, suggesting the high selectivity of ZM-412 to CIN tumors as monotherapy. Both KIF18A inhibitors and monomethyl auristatin E (MMAE) regulate microtubule dynamics, which provides a potential combination strategy. ZM-412 showed a significantly synergic effect with free MMAE or MMAE-conjugated ADC on the inhibition of proliferation in multiple kinds of cancer cell lines, including CIN-positive/negative tumor cell lines. In vivo, ZM-412 potently inhibited tumor growth in a dose-dependent manner in OVCAR3 and HT29 xenograft models. Moreover, ZM-412 showed a remarkable synergic effect on tumor growth inhibition with MMAE-conjugated LIV-1 ADC in OVCAR3 xenograft model. In conclusion, we discovered ZM-412 as a novel potent and selective KIF18A inhibitor, which has potential for the treatment of CIN cancers as monotherapy and for combination therapies for extended cancer types with MMAE-ADC. Citation Format: Feng Zhou, Lei Zhou, Ruina Wang, Liting Xue, Xiaokang Qin, Zhengtao Li, Jian Yu, Renhong Tang. ZM-412, a potent and selective KIF18A inhibitor with robust efficacy as monotherapy in CIN-positive tumors and in combination with MMAE-conjugated ADC in CIN-negative tumors [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(6_Suppl):Abstract nr 5946.