Background:
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.
Methods:
We have followed a structure-based virtual screening (SBVS) procedure with a library composed
of 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 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.
Results:
The whole six compounds displayed good effects when compared with erlotinib at 30 μM.
When reducing the concentration to 10μM, 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.
Conclusion:
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.
Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate
