The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that plays a critical role in the regulation of cell growth, proliferation, and differentiation [1]. It is expressed on the surface of neurons, epithelial and mesenchymal cells [2].
The EGFR signaling cascade is activated by binding specific ligands, such as epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), and amphiregulin (AREG), to the extracellular domain of the receptor. As a result, the receptor dimerizes and autophosphorylates tyrosine residues in the intracellular domain, which ultimately initiates Ras/MAPK and PI3K/Akt signaling pathways, eventually leading to cellular responses, in particular cell proliferation, survival, and migration [3-5].
When EGFR signaling is dysregulated, human lung, breast, colon, head and neck cancers can progress [6-9]. The development of these problems is associated with mutations in the EGFR gene that lead to constitutive activation of the receptor and, at the same time, to increased cell proliferation and survival. In addition to cancer, EGFR dysfunction can lead to the development of rheumatoid arthritis, asthma, and Alzheimer's disease [10-12].
The Life Chemicals chemoinformatics team has developed this new Docking Library of over 1,000 drug-like screening compounds that are potential inhibitors of the EGFR.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Figure 1. Examples of compounds with the best values of docking scores from the EGFR Kinase Targeted Library
Compound selection
High-throughput virtual screening and molecular fitting were performed on the 7K1I PDB structure [13] of EGFR against the Life Chemicals HTS Compound Collection. The compound selection was refined by PAINS, toxic and reactive filters, followed by the in-house MedChem filters to obtain over 1,000 drug-like screening compounds.
Key features:
- Method: high-throughput virtual screening (docking), molecular fitting
- X-Ray data used: 7K1I
- Constraints: no
- Filters used: PAINS, toxic, reactive
- Number of compounds selected: 1033
Figure 2. Spatial structure binding site of the complex of EGFR kinase with the lead docking molecule F1882-1540
References
- Sabbah DA, Hajjo R, Sweidan K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr Top Med Chem. 2020;20(10):815-834. doi:10.2174/1568026620666200303123102
- Yuan T, Ma H, Du Z, et al. Shp1 positively regulates EGFR signaling by controlling EGFR protein expression in mammary epithelial cells. Biochem Biophys Res Commun. 2017;488(3):439-444. doi:10.1016/j.bbrc.2017.04.072
- Yarden Y, Shilo BZ. SnapShot: EGFR signaling pathway. Cell. 2007;131(5):1018. doi:10.1016/j.cell.2007.11.013
- Tulpule A, Guan J, Neel DS, et al. Kinase-mediated RAS signaling via membrane-less cytoplasmic protein granules. Cell. 2021;184(10):2649-2664.e18. doi:10.1016/j.cell.2021.03.031
- Ersahin T, Tuncbag N, Cetin-Atalay R. The PI3K/AKT/mTOR interactive pathway. Mol Biosyst. 2015;11(7):1946-1954. doi:10.1039/c5mb00101c
- Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725-737. doi:10.1038/s41416-019-0573-8
- Li X, Zhao L, Chen C, Nie J, Jiao B. Can EGFR be a therapeutic target in breast cancer?. Biochim Biophys Acta Rev Cancer. 2022;1877(5):188789. doi:10.1016/j.bbcan.2022.188789
- Lian G, Chen S, Ouyang M, Li F, Chen L, Yang J. Colon Cancer Cell Secretes EGF to Promote M2 Polarization of TAM Through EGFR/PI3K/AKT/mTOR Pathway. Technol Cancer Res Treat. 2019;18:1533033819849068. doi:10.1177/1533033819849068
- Schinke H, Shi E, Lin Z, et al. A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer. Mol Cancer. 2022;21(1):178. Published 2022 Sep 8. doi:10.1186/s12943-022-01646-1
- Yuan FL, Li X, Lu WG, Sun JM, Jiang DL, Xu RS. Epidermal growth factor receptor (EGFR) as a therapeutic target in rheumatoid arthritis. Clin Rheumatol. 2013;32(3):289-292. doi:10.1007/s10067-012-2119-9
- Chen H, Gao Z, Cao X. Sheng Wu Gong Cheng Xue Bao. 2021;37(8):2870-2877. doi:10.13345/j.cjb.200618
- Mansour HM, Fawzy HM, El-Khatib AS, Khattab MM. Potential Repositioning of Anti-cancer EGFR Inhibitors in Alzheimer's Disease: Current Perspectives and Challenging Prospects. Neuroscience. 2021;469:191-196. doi:10.1016/j.neuroscience.2021.06.013
- Beyett TS, To C, Heppner DE, et al. Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. Nat Commun. 2022;13(1):2530. Published 2022 May 9. doi:10.1038/s41467-022-30258-y