Discovery of Novel Aromatic Urea-Imidazole Salt Derivatives for Cancer Therapy via Targeting ERK1/2

Extracellular signal-regulated kinases (ERKs) are pivotal signaling molecules in the RAS-RAF-MEK-ERK signaling pathway and have emerged as potential antitumor targets, providing a promising strategy for tumor therapy. Therefore, the development of antitumor drugs targeting ERK protein has received extensive attention. Here, we developed a compound library based on a series of novel aromatic urea-imidazole salt derivatives and conducted phenotypic screening against various cancer cell lines. Notably, 21y exhibited high efficacy against MCF-7 cells (IC50 = 0.67 μM). Furthermore, label-free drug affinity responsive target stability (DARTS) and LC-MS/MS proteomics techniques revealed that 21y directly targets ERK1/2. Mechanistically, 21y induced cell apoptosis and autophagy-related cell death. In vivo studies confirmed that 21y strongly inhibited tumor growth and lung metastasis in breast cancer. Taken together, 21y targets ERK1/2 as a promising therapeutic agent for breast cancer therapy.