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.