Structure-Based Virtual Screening for Defeating Drug Resistant Form of EGFR Protein.

  title={Structure-Based Virtual Screening for Defeating Drug Resistant Form of EGFR Protein.},
  author={Amirhossein Sharifi and Kowsar Bagherzadeh and Sahand Golestanian and Massoud Amanlou},
  journal={Combinatorial chemistry \& high throughput screening},
  volume={19 3},
Epidermal growth factor receptor (EGFR) is a tyrosine kinase with a key role in cell proliferation, death and differentiation. Mutations in EGFR, including substitution of Thr790 by methionine and Leu858 by arginine (T790M/L858R), lead to a lung cancer that is resistant against first generation inhibitors. In fact, second generation inhibitors were developed, but they proved to have had severe side effects because of the significant potency to suppress the wild type protein just as much. To… 
Structure-based pharmacophore design and virtual screening for novel potential inhibitors of epidermal growth factor receptor as an approach to breast cancer chemotherapy
Structural-based pharmacophore modeling, molecular docking and molecular dynamics simulations were applied to identify potential hits, which exhibited good inhibition on the proliferation of MCF-7 breast cancer cell line and favorable binding interactions on EGFR-TK.


Progress in structure-based design of EGFR inhibitors.
A computer-based protein engineering approach is elaborate demonstrating its potential to be a viable supplement to experiment in modulating the affinity of ligand molecules for EGFR in an efficient manner and the structural basis of the remarkable strategy is elucidated.
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
It is demonstrated that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors that may be clinically more effective and better tolerated than quinazoline-based inhibitors.
Superiority of a novel EGFR targeted covalent inhibitor over its reversible counterpart in overcoming drug resistance
The design of a novel pyrimidine-based irreversible inhibitor of EGFR (CNX17) is described which is active against both the WT EGFR as well as the resistance mutation L858R/T790M in biochemical assays.
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
It is concluded that the T790M mutation is a “generic” resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.
Structure-Based Approach for the Discovery of Pyrrolo[3,2-d]pyrimidine-Based EGFR T790M/L858R Mutant Inhibitors.
Crystal structures of the wild-type and T790M/L858R double mutant EGFR kinases with reversible and irreversible pyrrolo[3,2-d]pyrimidine inhibitors based on analogues of TAK-285 and neratinib are determined and provide structural insights for understanding the structure-activity relationships that should contribute to the development of potent inhibitors against drug-sensitive or -resistant EGFR mutations.
PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib.
Results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo, and these preclinical evaluations support further clinical development of PF00 299804 for cancers with mutations and/or amplifications of ERBB family members.
Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib.
  • E. Kwak, R. Sordella, D. Haber
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
These findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.
A novel treatment strategy for EGFR mutant NSCLC with T790M‐mediated acquired resistance
It is demonstrated that Gö6976 acts as a potent inhibitor of mutant EGFR despite the presence of T790M, the most important mechanism of acquired resistance for EGFR tyrosine kinase inhibitors, in both in vitro and in vivo models.
Computational Study of the Binding Mode of Epidermal Growth Factor Receptor Kinase Inhibitors
  • Haifeng Chen
  • Chemistry, Biology
    Chemical biology & drug design
  • 2008
The docking study and molecular dynamic simulation permit us to insight into the binding mode between ligand and EGFR kinase, and provide important information for structure‐based drug design.