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Targeting HER2-Positive HCC1954 Breast Cancer Cells by Novel Thiazole-Dihydrobenzisoxazoles: In-Depth Design,
Yuri A Piven1, Danila V Sorokin2, Nastassia A Varabyeva1
1Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, 220084, Belarus.
Background:
The most aggressive forms of breast cancer are characterized by independence from steroid hormones but a strong dependence on growth factors. In such cancer cells, oncogenic receptors, including human epidermal growth factor receptor 2 (HER2), are activated, and their targeted inhibition represents an attractive therapeutic strategy. The study aimed to develop small-molecule potential dual heat shock protein 90 (HSP90)-HER2 inhibitors and evaluate them as anticancer agents in HER2-positive cells.
Methods:
The research project involved obtaining a series of compounds with potential dual inhibitory activity against HSP90 and HER2 by targeted organic synthesis, which was preliminarily assessed using molecular modelling and calculation of key parameters of molecular dynamics. The potential therapeutic benefit of the obtained molecules was studied using basic molecular biological methods, including assessment of cytotoxic activity in vitro using the MTT test, as well as determination of a possible mechanism of action based on the expression of key participants in intracellular signaling (western blotting). Additionally, therapeutic combinations were developed and tested on a cellular model of the disease, including a lead compound and chemotherapeutic drugs used in clinical practice, in order to find synergistic pairs and improve the effectiveness of the treatment.
Results:
In this work, novel dual HSP90-HER2 inhibitors, based on the fused thiazole-dihydrobenzisoxazole polycyclic scaffold, were designed and synthesized. The resulting compounds exhibited strong antiproliferative activity against HER2-positive breast cancer cells with high selectivity. Among them, ATF-2 demonstrated antiproliferative activity comparable to HER2 inhibitor lapatinib and significantly suppressed HER2 expression and activity, epidermal growth factor receptor (EGFR) activity, and cyclin-dependent kinase 6 (CDK6) expression in HCC1954 breast cancer cells.
Conclusion:
These findings highlight ATF-2 as a promising dual HSP90-HER2 inhibitor with broader inhibitory effects on the HER2, EGFR, and CDK6 pathways.
Insights
Researchers developed novel dual heat shock protein 90 (HSP90)-HER2 inhibitors for aggressive breast cancer. Compound ATF-2 shows promise, inhibiting key pathways like HER2 and EGFR, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Aggressive breast cancers often resist hormone therapy but rely on growth factors.
- Human epidermal growth factor receptor 2 (HER2) is a key target in these cancers.
- Targeting oncogenic receptors like HER2 is a vital therapeutic strategy.
Purpose of the Study:
- To design and synthesize novel small-molecule dual inhibitors of heat shock protein 90 (HSP90) and HER2.
- To evaluate these inhibitors as potential anticancer agents for HER2-positive breast cancer cells.
- To explore therapeutic combinations for enhanced treatment efficacy.
Main Methods:
- Organic synthesis and molecular modeling were used to design and assess potential dual HSP90-HER2 inhibitors.
- In vitro cytotoxic activity was evaluated using the MTT assay.
- Mechanism of action was determined by analyzing key intracellular signaling proteins via western blotting.
Main Results:
- Novel dual HSP90-HER2 inhibitors were synthesized, exhibiting high selectivity and antiproliferative activity against HER2-positive breast cancer cells.
- Compound ATF-2 demonstrated efficacy comparable to lapatinib, suppressing HER2, EGFR, and CDK6.
- Therapeutic combinations were explored to identify synergistic drug pairs.
Conclusions:
- ATF-2 is a promising dual HSP90-HER2 inhibitor with significant potential for treating HER2-positive breast cancer.
- ATF-2 exhibits broad inhibitory effects on critical cancer pathways including HER2, EGFR, and CDK6.
- Further research into ATF-2 and its combinations could lead to improved breast cancer therapies.
