Targeting HER2-Positive HCC1954 Breast Cancer Cells by Novel Thiazole-Dihydrobenzisoxazoles: In-Depth Design, Synthesis and Initial In Vitro Study
Abstract
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…
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