Quinoline-5,8-dione CDC25 inhibitors: Potent anti-cancer agents in leukemia and patient-derived colorectal organoids.

Cell division cycle 25 (CDC25) phosphatases are critical activators of cyclin-dependent kinases (CDKs) and guardians of genome integrity, making them attractive anticancer targets. Building on the quinoline-5,8-dione scaffold NSC663284 (6a), we synthesized derivatives with diverse C-6/C-7 alkylamino side chains. Structure-activity studies identified D3a/D3b (2-(4-methylpiperidin-1-yl)ethylamino) and D11a/D11b (2-(dimethylamino)ethylamino) as the most potent, exhibiting low-submicromolar inhibition of CDC25. In cell-based assays, these compounds suppressed leukemia (IC50 0.21-1.22 μM) and colorectal cancer (IC50 0.13-1.50 μM) viability, with reduced toxicity in normal colonic epithelial cells. Mechanistically, these derivatives blocked CDC25-mediated CDK1 Tyr15 dephosphorylation, delayed G2/M progression, and induced caspase-dependent apoptosis with DNA damage. Cytotoxic potency correlated with baseline CDC25C expression, confirming on-target activity. Notably, efficacy was validated in colorectal cancer patient-derived organoids, providing clinically relevant insights into patient-specific responses. Together, these findings define a new class of CDC25 inhibitors with potent and selective anticancer activity, advancing prospects for next-generation therapeutics in leukemia and colorectal cancer.