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Life sciences · Journal article
Cell Biology and Toxicology · October 1, 2026
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Drug repurposing and the development of novel precursors are promising strategies for overcoming therapeutic resistance in breast cancer (BC). BnpM-NH₂, a hydroxyethylamino synthetic precursor of darunavir analogues, has previously demonstrated anticancer activity in haematological malignancies; however, its effects on BC remain unknown. This study investigated the antitumour activity of BnpM-NH₂, alone and in combination with tamoxifen (TMX), across molecularly distinct BC subtypes. Human BC cell lines representing hormone receptor-positive (MCF7), HER2-positive (SK-BR-3), and triple-negative (MDA-MB-231 and HCC1937) cell lines, together with non-tumorigenic MCF-10A cells, were treated with BnpM-NH₂ and/or TMX. Cell viability, proliferation, endoplasmic reticulum (ER) stress, autophagy, mitochondrial oxidative phosphorylation (OXPHOS), Akt–mTOR signalling, and apoptosis were evaluated using MTS assays, xCELLigence, and western blotting. Molecular docking and SwissADME analyses were used to evaluate target interactions and pharmacokinetic properties. BnpM-NH₂ significantly reduced BC cell viability with limited toxicity toward MCF-10A cells. Combination treatment with TMX enhanced the antiproliferative effects more than either agent alone. Mechanistically, BnpM-NH₂ modulated ER stress (ATF4, eIF2α), altered autophagy (LC3, p62), disrupted mitochondrial homeostasis through OXPHOS complexes and TOM20, modulated Akt–mTOR and S6 signalling, and activated caspase-dependent and apoptosis-inducing factor (AIF)-mediated mechanisms. Docking suggested favourable interactions of BnpM-NH₂ and tamoxifen with mTOR and Akt, and indicated that the two ligands can be accommodated simultaneously within adjacent regions of the respective binding pockets. SwissADME predicted favourable drug-likeness and high gastrointestinal absorption. BnpM-NH₂ exhibits broad antitumour activity across multiple BC subtypes and enhances the anticancer effects of tamoxifen. The combined experimental, computational, and pharmacokinetic prediction data support further preclinical evaluation of BnpM-NH₂ as a promising candidate for combination therapy in BC.