Recent Developments of Small Molecule EGFR Inhibitors Based on the Quinazoline Core Scaffolds

Abstract

Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells and associated with the development, progression and aggressiveness of a number of malignancies. Inhibition of EGFR signaling has thus been identified as an attractive strategy in control of tumor proliferation, and over a decade of intense activity in the field has culminated in the discoveries and subsequent approvals of gefitinib and erlotinib for the treatment of non-small cell lung cancer. However, the drug's resistance to gefitinib and erlotinib has been clinically observed. Therefore, intensive efforts have been made in the discovery of novel potent and selective EGFR inhibitors. This review will focus on the developments of small molecule EGFR inhibitors based on the quinazoline core scaffolds in recent 5 years. Diverse EGFR inhibitors are classified as 4-anilinoquinazolines and 4-nonanilininoquinazolines, their biological data are described, and the structure-activity relationships (SARs) are discussed.

Discovery of Potent EGFR Inhibitors through the Incorporation of a 3D‐Aromatic‐Boron‐Rich‐Cluster into the 4‐Anilinoquinazoline Scaffold: Potential Drugs for Glioma Treatment

“…The most extensively used agents in clinical research are both monoclonal antibodies directed against the extracellular receptor domain, such as cetuximab, and small molecules that bind reversible or irreversible into the catalytic pocket of EGFR, commonly known as tyrosine kinase inhibitors (TKIs) . Among those, molecules bearing the 4‐anilinoquinazoline core scaffold, such as gefitinib and erlotinib (Figure ), were found to be highly selective EGFR inhibitors and effective anticancer drugs. A broad spectrum of modifications of the 4‐anilinoquinazoline pharmacophore have been studied on the last decade in order to find more potent and selective TKIs .…”

An appraisal of anticancer activity with structure–activity relationship of quinazoline and quinazolinone analogues through EGFR and VEGFR inhibition: A review

“…Thus, the focus on 4-anilinoquinazoline will continue to find more active inhibitors of receptor tyrosine kinase. Other quinazoline derivatives like benzo-quinazoline, cinnamide quinazoline, or hybrids of quinazoline with thiophene, triazine, and imidazole were found very promising in terms of EGFR inhibitory activity (Bhatia et al, 2020;Das et al, 2020;Li et al, 2012;Y.-J. Liu et al, 2012).…”

“…Quinazoline and quinazolinone heterocycle‐based compounds have shown promising development as tubulin inhibitors, a polo‐like kinase inhibitor, EGFR inhibitor, and VEGFR inhibitor. Most of the quinazoline or quinazolinone‐based compounds exhibited potent inhibitory potency with efficacy in the nano‐molar range against EGFR and VEGFR kinases and several cancer cell lines (Bhatia et al, 2020; Das et al, 2020; Kavitha et al, 2018; Li et al, 2012; Liu et al, 2012; Srivastava et al, 2012).…”

Design, synthesis, crystal structure and biological evaluation of novel 4-arylaminoquin- azoline derivatives as potent cytotoxic agents

“…At present, some quinazoline drugs have been approved as antitumor drugs by the FDA, and widely used in clinical practice, especially in antitumor applications [13]. Since Gefitinib was used for targeted therapy of non-small cell lung cancer as the first generation EGFR-TKIs, it received extensive attention and small molecule targeted drugs had been greatly developed [14].…”