Abstract

Tamoxifen resistance remains a significant clinical challenge in breast cancer. The anti-apoptotic protein MCL1 is frequently overexpressed in tamoxifen-resistant tumors and is associated with poor patient survival, underscoring its potential as a therapeutic target. To identify novel MCL1 inhibitors, we first confirmed MCL1 upregulation in tamoxifen-resistant MCF7-R cells and clinical specimens. Using high-throughput virtual screening, molecular docking, and dynamics simulations, we identified capsazepine (CPZ) as a promising candidate. CPZ exhibited high binding affinity and formed stable interactions with key MCL1 residues, LEU267 and PHE270. Experimentally, CPZ significantly suppressed proliferation and induced mitochondrial-dependent apoptosis in MCF7-R cells. Importantly, CPZ synergized with tamoxifen to suppress colony formation and promote apoptosis, effectively reversing the resistant phenotype. Mechanistic studies using Drug Affinity Responsive Target Stability (DARTS) and functional assays confirmed that CPZ directly binds to and stabilizes MCL1. CPZ also demonstrated favorable drug-like properties and a superior predicted toxicity profile compared to the established inhibitor UMI-77. Our findings establish CPZ as a novel and effective MCL1 inhibitor that can help overcome tamoxifen resistance, offering a promising combined therapeutic strategy for endocrine-resistant breast cancer.