Small Molecule Inhibitors of the Epidermal Growth Factor Receptor

Abstract

The epidermal growth factor receptor (EGFR) has emerged over the past two decades as a key target in therapeutic approaches to the treatment of non-small cell lung cancer (NSCLC). This chapter describes the evolution of the EGFR small molecule inhibitor field, from early exploratory work and growing insight into the role of EGFR activating mutations, through to the first approved therapies, gefitinib and erlotinib. Advances in understanding resistance to these initial therapies and the role of the T790M mutation are discussed, along with drug discovery efforts culminating in the discovery of a number of EGFR mutant selective inhibitors, including osimertinib (TAGRISSO TM), the first approved treatment for patients with EGFR T790M mutation-positive metastatic NSCLC.

Structure-Based Drug Design Studies Toward the Discovery of Novel Chalcone Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors

“…Epidermal growth factor (EGF) or ErbB receptors belong to subclass I of the receptor tyrosine kinase protein’s family that consists of EGFR (ErbB1), HER2 (ErbB2, HER2/neu), HER3 (ErbB3), and HER4 (ErbB4) [1]. The three-dimensional structure of the EGFR is built up of three domains, namely; extracellular ligand binding domain region, transmembrane domain and cytoplasmic or an intracellular kinase domain [2].…”

Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors

“…Significant evidence suggests that all the first generation EGFR TKIs do not cross the blood–brain barrier (BBB) in concentrations sufficient to achieve therapeutic consequences in GBM tumors. − Although next-generation EGFR inhibitors, such as afatinib, dacomitinib, and neratinib, are still under clinical investigation for GBM, early data suggest minimal clinical activity for those EGFR TKIs in which patient outcomes are available. , The limited efficacy observed in GBM patients with these next-generation EGFR inhibitors may also be due to their inadequate brain exposure. , While the EGFR TKI osimertinibdeveloped for EGFR-mutated lung cancerhas reported high brain penetration, it has yet to be thoroughly evaluated either preclinically or clinically for GBM. Moreover, osimertinib does not effectively inhibit wtEGFR, which is presumably required to effectively target EGFR-driven GBMs . Thus, obtaining pharmacological levels of EGFR TKIs within GBM tumors, while also having potent activity against both wtEGFR and EGFRvIII, remains a major obstacle for their effective treatment.…”

“…From the extensive SAR work performed on the 4-anilinoquinazoline pharmacophore, as well as from the wealth of available structural information on the EGFR kinase domain, the essential binding interactions of this TKI scaffold are well-known. ,, An overview of the type I binding mode of erlotinib and, for comparison, the nonhydrolyzable ATP-analogue AMP-PNP is depicted in Figure S1.…”

“…9,10 While the EGFR TKI osimertinibdeveloped for EGFR-mutated lung cancerhas reported high brain penetration, 9 it has yet to be thoroughly evaluated either preclinically or clinically for GBM. Moreover, osimertinib does not effectively inhibit wtEGFR, 11 which is presumably required to effectively target EGFR-driven GBMs. 2 Thus, obtaining pharmacological levels of EGFR TKIs within GBM tumors, while also having potent activity against both wtEGFR and EGFRvIII, remains a major obstacle for their effective treatment.…”

“…Moreover, compounds 9 and 10 25 had reduced efficacy against EGFR compared to their 2′-fluorinated counterparts. The significance of the 2′-fluorine in protein−ligand binding was further accentuated by the substitution with a polar 2′-hydroxy group for the fluorine (11), which greatly reduced EGFR affinity. These results suggest a limitation of size and polarity of the 2′ substituent which is in line with previous studies.…”