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Review
. 2021 Feb 18;26(4):1076.
doi: 10.3390/molecules26041076.

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

Nichole E M Kaufman  1 , Simran Dhingra  1 , Seetharama D Jois  2 , Maria da Graça H Vicente  1
Affiliations
Review

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

Nichole E M Kaufman et al. Molecules. .

Abstract

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are two extensively studied membrane-bound receptor tyrosine kinase proteins that are frequently overexpressed in many cancers. As a result, these receptor families constitute attractive targets for imaging and therapeutic applications in the detection and treatment of cancer. This review explores the dynamic structure and structure-function relationships of these two growth factor receptors and their significance as it relates to theranostics of cancer, followed by some of the common inhibition modalities frequently employed to target EGFR and VEGFR, such as tyrosine kinase inhibitors (TKIs), antibodies, nanobodies, and peptides. A summary of the recent advances in molecular imaging techniques, including positron emission tomography (PET), single-photon emission computerized tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and optical imaging (OI), and in particular, near-IR fluorescence imaging using tetrapyrrolic-based fluorophores, concludes this review.

Keywords: EGFR; TKI; VEGFR; cancer; imaging; overexpression; peptide; protein; tyrosine kinase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A schematic diagram of the structure EGFR. (a) Full-length EGFR showing extracellular domain (ECD) in an open conformation, transmembrane (TM), and the cytoplasmic kinase domain. Published crystal structures of EGFR were used to prepare the schematic. ECD (PDB ID: 3NJP); transmembrane (PDB ID:2KS1), Kinase domain with juxtamembrane domain (PDB ID: 3GOP). Notice the distance between domains II and IV in an open conformation. Dimerization arm II is open for dimerization interaction. (b) Structure of ECD of EGFR in the closed conformation (PDB ID: 1NQL). Domains IV is folded and interacts with II. In the closed conformation EGFR dimerization arm II is not available for dimerization. PyMol (Schrodinger LLC. OR) was used to generate the structures of EGFR. ECD, extracellular domain; eJM, extracellualr juxtamembrane; TMD, transmembrane domain; iJM, intracellular juxtamembrane; TKD, tyrosine kinase domain [11,14,15,16].
Figure 2
Figure 2
Crystal structure of the kinase domain of EGFR (a) with ATP binding site highlighted (PDB ID: 2GS6). TKIs of EGFR bind to EGFR in the ATP binding pocket, forming 1 to 3 hydrogen bonds to the hinge region. (b) EGFR kinase domain with gefitinib bound in the ATP binding pocket (PDB ID: 3UG2). PyMol (Schrodinger LLC. OR, New York, NY, USA) was used to generate the figure [33,34].
Figure 3
Figure 3
(a) A schematic representation of full length VEGFR-1 with VEGF-A. Extracellular domains D1 to D6 are from the crystal structure of VEGFR-1 (PDB ID: 5T89). D7 and TM are shown in schematic. Kinase domain was from the crystal structure of VEGF (PDB ID: 3VHE). (b) Kinase domain of VEGF (PDB ID: 3VHE) showing hinge region and N and C-terminal lobes. PyMol (Schrodinger LLC. OR) was used to generate the figure [37,38].
Figure 4
Figure 4
Representative structures of first (1 and 2), second (3 and 4), third (5), and fourth (6) generation EGFR TKIs. Structures were generated using Chemdraw based on structures of TKIs available in selleckchem.com.
Figure 5
Figure 5
Binding modes of antibodies and nanobodies to EGFR extracellular domain. (a) Fab region of antibody cetuximab (red and yellow) bound to EGFR (green) domain III of ECD (PDB ID: 1YY9). (b) Panitumumab bound to EGFR ECD at domain III (PDB ID: 5SX4). (c) Crystal structure of nanobody bound to domain III of EGFR ECD. Only domain III is shown (PDB ID: 4KRl). PyMol (Schrodinger LLC. OR) was used to generate the figure [72,73].
Figure 6
Figure 6
Structures of EGFR-targeting peptides, EGFR-L1 and EGFR-L2.
Figure 7
Figure 7
Structures of peptide ligands on their binding sites: (a) EGFR-L1 in domain I, and (b) EGFR-L2 in the EGF binding pocket (PDB ID: 1NQL) proposed based on docking studies. Peptides are shown as sticks, and EGFR is shown in surface representation. This figure was reprinted with permission from Reference [83].
Figure 8
Figure 8
Structures of fluorophores conjugated to EGFR-L1 and EGFR-L2 peptides.
Figure 9
Figure 9
Structures of fluorophores conjugated to TKIs.
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References

    1. Moser C., Lang S.A., Stoeltzing O. The direct effects of anti-vascular endothelial growth factor therapy in tumor cells. Clin. Colorectal Cancer. 2007;6:564–571. doi: 10.3816/CCC.2007.n.023. - DOI - PubMed
    1. Sigismund S., Avanzato D., Lanzetti L. Emerging functions of the EGFR in cancer. Mol. Oncol. 2018;12:3–20. doi: 10.1002/1878-0261.12155. - DOI - PMC - PubMed
    1. Roskoski R., Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Phamacol. Res. 2016;103:26–48. doi: 10.1016/j.phrs.2015.10.021. - DOI - PubMed
    1. Roskoski R., Jr. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Phamacol. Res. 2019;139:395–411. doi: 10.1016/j.phrs.2018.11.014. - DOI - PubMed
    1. Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J. Biol. Chem. 1962;237:1555–1562. doi: 10.1016/S0021-9258(19)83739-0. - DOI - PubMed

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