Recent Advances in Drug Design of Epidermal Growth Factor Receptor Inhibitors
P. Warnault, A. Yasri, M. Coisy-Quivy, G. Cheve, C. Bories, B. Fauvel and R. Benhida
Affiliation: Equipe Molecules Bioactives, Institut de Chimie de Nice, UMR UNS CNRS 7272. Universite de Nice Sophia Antipolis. Parc Valrose, 06108 Nice cedex 2. France.
Keywords: Breast cancer, drug design, EGFR, irreversible inhibitors, NSCLC, mutation, reversible inhibitors
The tyrosine kinase epidermal growth factor receptor (EGFR) has emerged in recent years as a key and validated
target of targeted therapies for solid tumors. It plays a central role in oncology since it is involved in many steps of
tumor progression such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Recent
advances in targeted therapies have demonstrated that tyrosine kinase inhibitors (TKIs), have provided a marked
benefit to subsets of patients whose tumors harbor specific genetic abnormalities. However, resistance phenomenon appears
rapidly and patients with EGFR mutations acquire resistance to TKI inhibitors decreasing therefore the median time
to disease progression to few months. Several strategies were envisioned to overcome this resistance, such as dual–target
inhibitors, multitarget and combined therapy. This review summarizes recent advances in TKIs development with special
focus on rational strategies for the design of potent EGFR inhibitors including molecular modeling studies based on crystallographic
data. Such advances open the way for new research possibilities in modern medicinal chemistry combined to
structure-based drug design.
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