<p>This study aimed to introduce a synergistic integration platform based on single-cell and proteotranscriptomics for drug repositioning (SIMD) to repurpose breast cancer drug candidates by considering the bidirectional nature of molecular dynamics in protein transcriptomics and tumor heterogeneity at the single-cell level. SMID consists of two core methods: the anti-correlated proteotranscriptome perturbation score (ACPS), which measures the negative correlation between perturbagen-induced expression signatures and multi-omic expression profiles from patient-derived breast cancer samples; and perturbagen repositioning scoring and scRNA-seq data (PPNE), which ranks perturbagens exhibiting high ACPS scores and inverse transcriptomic associations with neoplastic epithelial (NE) cells identified through single-cell RNA sequencing data. We validated the top five SIMD-prioritized perturbagens by assessing cell viability in five breast cancer cell lines. Many perturbagens ranked highest by the ACPS have been ascertained in clinical trials for breast cancer or other cancer treatments. Validation revealed a substantial reduction in cell viability for the majority of perturbagens in most cell types. Our result observed significantly overexpressed phosphorylation sites within the AKT1 and PI3K genes, which are buparlisib target genes, suggesting that buparlisib may exert its effects across a spectrum of breast cancer types, including triple-negative breast cancer, by modulating molecular mechanisms within the PI3K pathway.</p>