Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors
- 24 August 2020
- journal article
- research article
- Published by Bentham Science Publishers Ltd. in Current Topics in Medicinal Chemistry
- Vol. 20 (18), 1628-1639
- https://doi.org/10.2174/1568026620666200603122726
Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. We have followed a structure-based virtual screening (SBVS) procedure with a library composed by several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to a positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10 μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.Keywords
Funding Information
- Agencia Estatal de Investigación of Spain (DI-17-09598/AEI)
This publication has 36 references indexed in Scilit:
- Mechanisms of Resistance to Epidermal Growth Factor Receptor Inhibitors and Novel Therapeutic Strategies to Overcome Resistance in NSCLC PatientsChemotherapy Research and Practice, 2012
- Targeting the EGFR signaling pathway in cancer therapyEmerging Therapeutic Targets, 2012
- Receptor-Based Virtual Screening of EGFR Kinase Inhibitors from the NCI Diversity DatabaseMolecules, 2010
- EGF–ERBB signalling: towards the systems levelNature Reviews Molecular Cell Biology, 2006
- Epidermal growth factor receptor (EGFR) signaling in cancerGene, 2006
- Epidermal growth factor receptor inhibition strategies in oncologyEndocrine-Related Cancer, 2004
- Structure and Function of the Epidermal Growth Factor (EGF⧸ErbB) Family of ReceptorsAdvances in protein chemistry, 2004
- Epidermal growth factor receptor: mechanisms of activation and signallingExperimental Cell Research, 2003
- EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy.Folia Pharmacologica Japonica, 2003
- Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular DomainsCell, 2002