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

  • Eur J Med Chem. 2026 Jan 5:301:118215. doi: 10.1016/j.ejmech.2025.118215.
Iin Narwanti  1 ,  Zih-Yao Yu  2 ,  Bidyadhar Sethy  3 ,  Pei-Ling Zheng  2 ,  Li-Hsin Cheng  4 ,  Kelvin K Tsai  4 ,  Sung-Bau Lee  5 ,  Jing-Ping Liou  6
Affiliations
  • 1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Indonesia.
  • 2. Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 3. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 4. Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Core Laboratory of Organoids Technology, Office of R&D, Taipei Medical University, Taipei, Taiwan.
  • 5. Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
  • 6. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
PMID: 41045697 DOI: 10.1016/j.ejmech.2025.118215
Abstract

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.

Keywords
CDC25 inhibitors; Cancer therapeutics; Cell cycle arrest; Genomic instability; Patient-derived organoids; Quinoline-5,8-dione.
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