Abstract 7094: Discovery of QLS1303, a potent and selective KIF18A inhibitor with robust anti-tumor activity in CIN+ preclinical cancer models

Abstract Background: Chromosomal instability (CIN) underlies the aneuploidy present in ∼90 % of solid tumors and engenders a persistent requirement for the plus-end kinesin KIF18A to silence mitotic checkpoints and align extra chromosomes. Consequently, KIF18A inhibition triggers catastrophic mis-segregation exclusively in CIN-high cells, inducing mitotic arrest or apoptosis, while sparing normal diploid cells. This synthetic-lethal interaction makes KIF18A as an attractive, cancer-selective therapeutic target, which prompted multiple drug-discovery programs, including AMG 650, a clinical-stage KIF18A inhibitor. Here we report the discovery and preclinical profiling of QLS1303, a novel, potent and orally bioavailable KIF18A inhibitor engineered to against aneuploid cancers with CIN-specific vulnerability. Experimental Procedures: The inhibitory activity of QLS1303 was assessed through biochemical (KIF18A motor activity) and cellular proliferation assays using CIN+ and near-diploid cancer cell lines. In vivo efficacy and tolerability were evaluated in TP53mut/aneuploidy-high CDX models following once-daily oral administration. Selectivity and safety were profiled against a panel of 46 safety targets. Results: QLS1303 potently inhibited KIF18A motor activity (IC50 = 13 nM) with a good selectivity over known toxic kinesin family members. It selectively suppressed proliferation of CIN+ cell lines (IC50 = 4-14 nM) with minimal effects on near-diploid cells. Once-daily oral administration of QLS1303 at 3 and 10 mg/kg was well-tolerated and induced tumor regression in multiple TP53mut/aneuploidy-high CDX models, and achieved tumor stasis at one-tenth of AMG 650 dosage in OVCAR3 xenograft model. A clean selectivity and safety profile were confirmed with no significant inhibition (IC50 10 µM) across the 46-target panel. In addition, QLS1303 exhibits favorable drug-like properties and a promising predicted therapeutic window. Conclusion: QLS1303 is a highly potent, selective, and orally bioavailable KIF18A inhibitor, demonstrating robust anti-tumor activity in CIN+ preclinical models and a compelling safety profile. These data strongly support its advancement into clinical studies. Citation Format: Fei Chen, Wei Wei, Xiaobing Lv, Xiaoping Zheng, Chen Yang, Lili Fan, Fang Zhang, Junguo Hao, Xinrui Shao, Yan Wu, Ling Li, Ping Chen, Dong Yang, Hua Dong, Guqing Shi, Dongdong Wu, Yanling Xu, Weimei Sun, Liang Xie, Wenyuan Qian, Daqing Sun, Weikang Tao. Discovery of QLS1303, a potent and selective KIF18A inhibitor with robust anti-tumor activity in CIN+ preclinical cancer models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7094.