Butein suppresses pancreatic cancer progression by downregulating CDK2 and disrupting CDK2/CyclinA2 interaction.

Pancreatic cancer is a highly lethal malignancy with limited therapeutic options. Our study identifies butein, a natural chalcone from Plumbago species, as a powerful anti-tumor agent against pancreatic cancer. Integrated in silico molecular docking and cellular biophysical assays, including Cellular Thermal Shift Assay (CETSA) and Drug Affinity Responsive Target Stability (DARTS), confirmed that CDK2 is a direct binding target of butein. Butein exerts its effects by arresting the cell cycle at the G2/M phase, inducing apoptosis, and significantly inhibiting the proliferation of pancreatic cancer cells. Further analysis revealed that butein downregulates CDK2 expression and disrupts its interaction with cyclinA2. Genetic validation confirmed CDK2 as the critical mediator of butein's efficacy that CDK2 overexpression conferred resistance, whereas its knockdown synergized with butein. In mouse xenograft models, butein treatment markedly inhibited tumor growth without observable systemic toxicity. Our findings highlight butein as a promising CDK2 inhibitor, presenting a novel and translatable therapeutic strategy for pancreatic cancer.