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

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.