Design, synthesis and optimization of Apcin analogues as Cdc20 inhibitors for triple-negative breast cancer therapy
Xiangyang Le1, Qingsong Chen2, Qiwan Wen2
1Department 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.
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.
Insights
A novel compound, 14c, effectively inhibits Cdc20, a key protein in triple-negative breast cancer (TNBC) cell division. This targeted approach shows significant promise for treating aggressive TNBC with minimal toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Overexpression of Cell division cycle 20 homologue (Cdc20) is linked to triple-negative breast cancer (TNBC) progression and poor outcomes.
- Targeting Cdc20 presents a potential therapeutic strategy for TNBC.
- Apcin analogues were explored as potential Cdc20 inhibitors.
Purpose of the Study:
- To optimize Apcin analogues as Cdc20 inhibitors using a receptor-based drug design.
- To identify a potent and selective Cdc20 inhibitor for TNBC treatment.
Main Methods:
- A two-step drug design strategy: concept validation and structural optimization.
- In vitro assays to assess Cdc20 binding affinity, antiproliferative effects, and selectivity.
- In vivo studies using a TNBC xenograft model.
Main Results:
- Compound 14c exhibited strong Cdc20 binding (KD: 7.65 μM) and potent antiproliferative activity against TNBC cells (IC50: 3.28 μM).
- 14c demonstrated favorable selectivity, inhibiting Cdc20, inducing G2/M arrest, DNA damage, and apoptosis, while suppressing tumor growth in vivo by 90% with no observed toxicity.
- Key substrates like Cyclin B1 and Bim were stabilized by 14c.
Conclusions:
- Compound 14c is a potent Cdc20 inhibitor with significant therapeutic potential for TNBC.
- The identified compound offers a promising new avenue for TNBC treatment due to its efficacy and safety profile.
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