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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Extracellular signal-regulated kinases (ERKs) are key components of the RAS-RAF-MEK-ERK pathway, making them significant targets for cancer therapy.
• Developing novel antitumor drugs targeting ERK signaling is a critical area of research for effective cancer treatment.

Purpose of the Study:

• To develop and evaluate novel aromatic urea-imidazole salt derivatives as potential ERK inhibitors.
• To identify specific compounds with high efficacy against cancer cell lines and elucidate their mechanism of action.

Main Methods:

• Phenotypic screening of a novel compound library against various cancer cell lines.
• Label-free drug affinity responsive target stability (DARTS) and LC-MS/MS proteomics to identify drug targets.
• In vitro assays to assess apoptosis and autophagy.
• In vivo studies in animal models to evaluate therapeutic efficacy.

Main Results:

• Compound 21y demonstrated high efficacy against MCF-7 cells with an IC50 of 0.67 μM.
• DARTS and proteomics confirmed that 21y directly targets ERK1/2.
• 21y induced cancer cell apoptosis and autophagy-related cell death.
• In vivo studies showed significant inhibition of tumor growth and lung metastasis in breast cancer models.

Conclusions:

• Compound 21y is a potent inhibitor of ERK1/2.
• 21y exhibits significant antitumor activity and anti-metastatic effects in preclinical breast cancer models.
• 21y represents a promising therapeutic candidate for breast cancer treatment targeting the ERK pathway.