2. Academic Validation
  3. Design, synthesis and optimization of Apcin analogues as Cdc20 inhibitors for triple-negative breast cancer therapy

Design, synthesis and optimization of Apcin analogues as Cdc20 inhibitors for triple-negative breast cancer therapy

  • Eur J Med Chem. 2025 May 5:289:117434. doi: 10.1016/j.ejmech.2025.117434.
Xiangyang Le 1,  Qingsong Chen 2,  Qiwan Wen 2,  Shuyang Cao 2,  Lei Zhang 2,  Liqing Hu 3,  Gaoyun Hu 2,  Qianbin Li 2,  Zhuo Chen 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Department of Pharmacy, Yiyang Central Hospital, Yiyang, Hunan, 413000, China.
  • 2 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China.
  • 3 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Pharmaceutical Sciences, Hunan Normal University, Changsha, 410013, Hunan, China.
  • 4 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China. Electronic address: cz_job@csu.edu.cn.
PMID: 40020424 DOI: 10.1016/j.ejmech.2025.117434
Abstract

Cell division cycle 20 homologue (Cdc20) is an essential mitotic regulator whose overexpression is closely associated with tumorigenesis and poor prognosis in triple-negative breast Cancer (TNBC). Targeting Cdc20 has therefore emerged as a promising therapeutic avenue for this aggressive malignancy. In the present study, a receptor-based drug design approach was employed to optimize Apcin analogues as Cdc20 inhibitors. Through a two-step strategy-concept validation followed by structural optimization-we identified compound 14c, which demonstrated remarkable Cdc20 binding affinity (KD: 7.65 μM), potent antiproliferative effects against MDA-MB-231 TNBC cells (IC50: 3.28 μM), and a favorable selectivity index (4.22 for MCF-7 non-TNBC cells and 7.27 for MCF 10A normal cells). 14c effectively inhibited Cdc20 activity, induced G2/M phase arrest, promoted DNA damage accumulation, and stabilized key substrates such as Cyclin B1 and Bim, leading to enhanced Apoptosis and suppression of tumor cell proliferation and migration. In vivo, 14c significantly inhibited tumor growth in an MDA-MB-231 xenograft model with a 90 % tumor inhibition rate and no observable toxicity. These results highlight the potential of 14c as a potent Cdc20 inhibitor, offering a promising therapeutic approach for TNBC.

Keywords

Apcin analogues; Cell division cycle 20 homologue; Inhibitors; Triple-negative breast cancer.

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