RB‐BC: A Novel Ribociclib Derivative Targeting p53‐Mediated Apoptosis and Inhibition of Tumor Growth in Breast Cancer

Breast cancer persists as the most prevalent malignancy and principal contributor to cancer-associated mortality among women worldwide, exhibiting marked disease heterogeneity and therapeutic resistance. Consequently, the development of novel therapeutic agents remains imperative. Ribociclib, a cyclin-dependent kinase 4/6 inhibitor, has emerged as a focus in adjuvant breast cancer research due to its mechanism of cell cycle arrest induction. Building upon this rationale, we designed and synthesized a novel Ribociclib derivative, RB-BC, systematically investigating its anti-neoplastic efficacy and molecular mechanisms in breast cancer through an integrated in vitro and in vivo experimental system. The compound's anti-proliferative effects were quantitatively assessed via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, 5-ethynyl-2'-deoxyuridine incorporation assays, and colony formation assays. Functional characterization through cell adhesion assays, scratch wound healing assays, and Transwell invasion assays demonstrated RB-BC's dose-dependent suppression of tumor migration and invasion. Mechanistic analyses, conducted via RNA sequencing and Western blotting, revealed that its anti-tumor activity primarily stems from the activation of the p53 pathway, which induces caspase-3-mediated apoptosis in breast cancer cells. Machine learning algorithms identified p53-associated genetic signatures, and subsequent bioinformatics analyses elucidated their significant correlation with immune cell infiltration dynamics in the tumor microenvironment. Moreover, RB-BC effectively suppressed tumor growth in vivo and significantly disrupted angiogenesis in the chick chorioallantoic membrane assay. In summary, the Ribociclib-derived compound, RB-BC, demonstrates compelling potential as a candidate therapeutic agent for breast cancer.