Discovery of novel imidazopyrazine derivative as a KIF18A inhibitor.

KIF18A, a plus-end mitotic kinesin critical for spindle integrity in chromosomally unstable (CIN) tumors, represents a synthetic-lethal target for anti-mitotic therapy. Herein we report the discovery of compound 19d, a novel imidazopyrazine featuring a spiro-bridged amine that potently inhibits KIF18A (IC50 = 52 nM) and exhibits single-digit nanomolar antiproliferative activity in CIN-high OVCAR-3 cells (EC50 = 3.4 nM) with selectivity over CIN-low HCT116 cells (EC50 > 2 μM). Compound 19d displays prolonged plasma half-life across mouse, rat, and dog, enabling sustained systemic exposure. Once-daily oral administration of 19d (5 mg/kg) drives complete tumor regression in the OVCAR-3 xenograft model without body-weight loss. These findings support the continued preclinical evaluation of 19d, including expanded efficacy studies, comprehensive toxicology, and tumor PK/PD assessment.