Review on EGFR Inhibitors: Critical Updates

Abstract

Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein that constitutes one of the four members of ErbB family of tyrosine kinase receptors. Activation of EGFR leads to autophosphorylation of receptor tyrosine kinase that initiates a cascade of downstream signaling pathways involved in regulating cellular proliferation, differentiation, and survival. EGFR is abnormally activated by various mechanisms like receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation and is associated with the development of variety of human cancers. EGFR inhibition is one of the key targets for cancer chemotherapy. Approval of tyrosine kinase inhibitors such as erlotinib, gefitinib, and lapatinib for the treatment of non-small cell lung cancer led to tremendous development of novel EGFR inhibitors in the last decade. Diverse class of chemical compounds from the synthetic origin has been extensively studied. This review highlights the various classes of synthetically derived molecules which have been reported in the last few years as potential EGFR and EGFR/ErbB-2 dual inhibitors. A brief synthetic methodology to access these compounds has been highlighted along with the SAR. We strongly believe that this review will provide a platform to the synthetic chemists and biologists to design and synthesize new and potent compounds that inhibit EGFR and ErbB-2.

Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib

“…They found that the L858R mutation results in additional electrostatic interactions between R858 and the negatively charged residues E758, E762 or D761 from the αC-helix, resulting in reduced flexibility and stabilization of the KD in its active state. Co-crystal structures 8 of inhibitors complexed to the KD of EGFR paved the path for the rational design of several second and third generation drugs to deal with the resistance mutations 8 including the covalent inhibitor afatinib for treating EGFR L858R and EGFR 19del . In stably transfected EGFR mutant isogenic cell line models, afatinib inhibited phosphorylation in EGFR 19del models to a higher extent than in EGFR L858R , a finding that was not observed with reversible EGFR TKI 9 .…”

Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models

“…Using phosphotyrosine arrays, we observed expression of activated ERBB1 and ERBB3 in many Ewing sarcoma cell lines. 25 Thus, it was of interest to evaluate the ERBB3-targeted antibody patritumab alone or combined with erlotinib, a small molecule inhibitor of ERBB1/2, 26 and to evaluate if either drug or these drugs in combination had significant antitumor activity. As development of such targeted therapeutics will involve integration with cytotoxic agents, we asked whether these agents could enhance the activity of standard of care cytotoxic therapy used in the treatment of childhood sarcomas.…”

Preliminary mechanisms of regulating PD‑L1 expression in non‑small cell lung cancer during the EMT process

“…Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancer cases (26). Since 2003, three generations of TKI drugs have received FDA approval for the clinical treatment of NSCLC (27). However, the increasing rate of drug resistance in patients treated with chemotherapy increasingly becomes a serious challenge; even patients who are sensitive to chemotherapeutic drugs at the start of treatment develop resistance within a few months (28).…”