Novel Aza-podophyllotoxin Derivative Inhibits Growth of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), the most aggressive type of breast cancer, has high rates of metastasis and recurrence and represents 15-20% of diagnosed breast cancer cases. Most women with TNBC experience recurrence following curative treatment for early-stage breast cancer. We have identified CET022, a novel small molecule, and shown that it inhibits TNBC growth and clonogenic potential in multiple cell lines (MDA-MB-231, MDA-MB-468, 4T1, and EMT6). Further, CET022 treatment results in G2/M phase cell-cycle arrest and apoptosis. The proteomic analysis has identified metabolic pathways as the key target of CET022 and the reduction of metabolic enzyme Enolase-3, which is a crucial regulator in the second half of the glycolysis pathway and is responsible for the conversion of 2-phosphoglycerate to phosphoenolpyruvate. Overall, our study provides the foundation for the further development of CET022 as a potential therapeutic candidate to treat patients with TNBCs.