2. Academic Validation
  3. First-in-Class Quinoline-Dione-Derived PROTACs: Potent Degraders of Cdc25 Phosphatases for Antitumor Therapy

First-in-Class Quinoline-Dione-Derived PROTACs: Potent Degraders of Cdc25 Phosphatases for Antitumor Therapy

  • J Med Chem. 2026 Jan 22;69(2):982-1003. doi: 10.1021/acs.jmedchem.5c02112.
Guanyu Dong 1,  Mengfei Chen 2,  Xiangyi Jiang 1,  Jing Shi 2,  Xiangjiao Meng 2,  Peng Zhan 1,  Yuguo Liu 2,  Chuanfeng Liu 2 3,  Yuning Song 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China.
  • 2 Department of Pharmacy (Shandong Provincial Key Traditional Chinese Medical Discipline of Clinical Chinese Pharmacy), Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, P. R. China.
  • 3 Suzhou Research Institute of Shandong University, Room607, Building B of NUSP, NO.388 Ruoshui Road, SIP, Suzhou, Jiangsu 215123, P. R. China.
  • 4 Department of Pharmacy, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P. R. China.
PMID: 41507075 DOI: 10.1021/acs.jmedchem.5c02112
Abstract

Dysregulated Cdc25 phosphatases drive tumorigenesis, but their "undruggable" active site (planar and electropositive) has hindered small-molecule inhibitor development. Herein, we report the first-in-class PROTAC degraders targeting Cdc25, derived from the quinoline-dione scaffold, by conjugating NSC663284 (a Cdc25 inhibitor) with E3 Ligase ligands via optimized linkers. Among them, compound D3, the most potent degrader, induced concentration- and time-dependent degradation of Cdc25A/B/C with DC50 values of 0.97 μM, 2.02 μM, and 4.67 μM, respectively, via a proteasome-dependent pathway. D3 can significantly inhibit tumor growth in xenotransplantation models and exhibit a favorable pharmacokinetic profile. Mechanistically, D3 exerts antitumor effects by degrading the target protein Cdc25, upregulating p-CDK1/2 levels, and subsequently inducing G2/M phase cell cycle arrest and Apoptosis. This study validates PROTACs as a breakthrough strategy to target "undruggable" Cdc25, provides a novel quinoline-dione-based scaffold for antitumor drug development, and offers a rational design paradigm for tackling intractable Phosphatase targets.

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