Quinoline-5,8-Dione CDC25 Inhibitors: Potent Anti-Cancer Agents in Leukemia and Patient-Derived Colorectal Organoids

Cell division cycle 25 (CDC25) phosphatases have emerged as critical regulators of cell cycle progression and genomic stability, making them compelling therapeutic targets in oncology. Building on the established CDC25 inhibitor NSC663284 , we strategically designed, synthesized, and evaluated a novel series of derivatives with diverse alkylamino side chains to enhance potency and selectivity. Among them, derivatives featuring 2-(4-methylpiperidin-1-yl)ethylamino ( D3a and D3b ) or 2-(dimethylamino)ethylamino groups ( D11a and D11b ) demonstrated remarkable anti-cancer efficacy, exhibiting potent apoptotic induction and broad-spectrum growth inhibition. These compounds displayed IC ₅₀ values between 0.21 to 1.22 μM in leukemia cells and from 0.13 to 1.5 μM in CRC cells, surpassing the activity of NSC663284 . Mechanistically, these derivatives effectively inhibited CDC25 phosphatase activity in vitro and disrupted CDC25-mediated dephosphorylation of CDK1 in cells, leading to cell cycle arrest and catastrophic genomic instability. Treatment with these compounds induced rapid and extensive double-stranded DNA breaks, highlighting their potential to drive irreversible cancer cell death. Importantly, their therapeutic potential was further validated in CRC patient-derived tumor organoids, offering clinically relevant insights into patient-specific drug responses and underscoring their translational significance. Our findings establish a new class of CDC25 inhibitors with superior anti-cancer activity and mechanistic precision, paving the way for next-generation therapeutics targeting leukemia and CRC.