Preliminary Discovery of Small Molecule Inhibitors of Epidermal Growth Factor Receptor (EGFR) That Bind to the Extracellular Domain

Abstract

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein belonging to the protein kinase superfamily. It is composed of an extracellular domain, a transmembrane anchoring region and a cytoplasmic region endowed with tyrosine kinase activity. Genetic mutations of EGFR kinase cause higher activity thereby stimulating downstream signaling pathways that, in turn, impact transcription and cell cycle progression. Due to the involvement of mutant EGFR in tumors and inflammatory diseases, in the past decade, several EGFR inhibitory strategies have been extensively studied, either targeting the extracellular domain (through monoclonal antibodies) or the intracellular kinase domain (through ATP-mimic small molecules). Monoclonal antibodies impair the binding to growth factor, the receptor dimerization, and its activation, whereas small molecules block the intracellular catalytic activity. Herein, we describe the development of a novel small molecule, called DSF-102, that interacts with the extracellular domain of EGFR. When tested in vitro in KRAS mutant A549 cells, it impairs EGFR activity by exerting (i) dose-dependent toxicity effects; (ii) a negative regulation of ERK, MAPK p38 and AKT; and (iii) a modulation of the intracellular trafficking and lysosomal degradation of EGFR. Interestingly, DSF-102 exerts its EGFR inhibitory activity without showing interaction with the intracellular kinase domain. Taken together, these findings suggest that DSF-102 is a promising hit compound for the development of a novel class of anti-EGFR compounds, i.e., small molecules able to interact with the extracellular domain of EGFR and useful for overcoming the KRAS-driven resistance to TKI treatment.

Isorhamnetin Regulates Programmed Death Ligand-1 Expression by Suppressing the EGFR–STAT3 Signaling Pathway in Canine Mammary Tumors

“…Therefore, there is an urgent need to find and develop new drugs to treat canine mammary tumors. Epidermal growth factor receptor (EGFR) is a member of the epidermal growth factor receptor family and comprises an extracellular ligand-binding region, a transmembrane region, and an intracellular kinase region [7]. It is widely distributed on the surface of mammalian cells and has an important role in physiological processes, including the growth, proliferation, and differentiation of cancer cells [8].…”

Recent Advancements, Limitations, and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer

“… 124 It selectively binds to the extracellular region of the EGFR and blocks the domain from binding to epidermal growth factor (EGF) and other ligands. 125 This blockage results in cell growth inhibition, increased apoptosis of tumor cells, reduced angiogenesis, and metastasis. 126 It is a first-line colon cancer drug used along with chemotherapy.…”