Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold

2018 ◽  
Vol 61 (24) ◽  
pp. 11372-11383 ◽  
Author(s):  
Yilan Ju ◽  
Jintao Wu ◽  
Xi Yuan ◽  
Luqing Zhao ◽  
Ganlin Zhang ◽  
...  
Keyword(s):  
Egfr Inhibitors ◽  
Macrocyclic Polyamine

EGFR Inhibitors in Treatment of Lung Adenocarcinoma

2014 ◽  
Vol 10 (Issue 3-4) ◽  
pp. 47-55
Author(s):  
Ehab Ibrahim
Keyword(s):  
Lung Adenocarcinoma ◽  
Egfr Inhibitors

Irreversible EGFR Inhibitors in the Treatment of Advanced NSCLC

2014 ◽  
Vol 20 (24) ◽  
pp. 3894-3900 ◽  
Author(s):  
Paolo Maione ◽  
Antonio Rossi ◽  
Marianna Bareschino ◽  
Paola Sacco ◽  
Clorinda Schettino ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Egfr Inhibitors

Clinical results with EGFR inhibitors in colorectal cancer

2012 ◽  
pp. 44-59
Author(s):  
Erika Martinelli ◽  
Teresa Troiani ◽  
Floriana Morgillo ◽  
Fortunato Ciardiello
Keyword(s):  
Colorectal Cancer ◽  
Clinical Results ◽  
Egfr Inhibitors

New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: synthesis, anticancer, antimicrobial evaluation and computational studies

2021 ◽  
pp. 105078
Author(s):  
Ismail M. M. Othman ◽  
Zahra M. Alamshany ◽  
Nada Y. Tashkandi ◽  
Mohamed A.M. Gad-Elkareem ◽  
Manal M. Anwar ◽  
...  
Keyword(s):  
Egfr Inhibitors ◽  
Computational Studies ◽  
Antimicrobial Evaluation

scholarly journals A Reversible Shift of Driver Dependence from EGFR to Notch1 in Non-Small Cell Lung Cancer as a Cause of Resistance to Tyrosine Kinase Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2022
Author(s):  
Francesca Iommelli ◽  
Viviana De Rosa ◽  
Cristina Terlizzi ◽  
Rosa Fonti ◽  
Rosa Camerlingo ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Parental Cell ◽  
Egfr Inhibitors ◽  
Simultaneous Increase ◽  
Adherent Cells ◽  
Binding Assays ◽  
Mesenchymal Transition ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Notch1 plays a key role in epithelial-mesenchymal transition (EMT) and in the maintenance of cancer stem cells. In the present study we tested whether high levels of activated Notch1 in oncogene-driven NSCLC can induce a reversible shift of driver dependence from EGFR to Notch1, and thus causing resistance to EGFR inhibitors. Adherent cells (parental) and tumor spheres (TS) from NSCLC H1975 cells and patient-derived CD133-positive cells were tested for EGFR and Notch1 signaling cascade. The Notch1-dependent modulation of EGFR, NCID, Hes1, p53, and Sp1 were then analyzed in parental cells by binding assays with a Notch1 agonist, DLL4. TS were more resistant than parental cells to EGFR inhibitors. A strong upregulation of Notch1 and a concomitant downregulation of EGFR were observed in TS compared to parental cells. Parental cell exposure to DLL4 showed a dose-dependent decrease of EGFR and a simultaneous increase of NCID, Hes1, p53, and Sp1, along with the dislocation of Sp1 from the EGFR promoter. Furthermore, an enhanced interaction between p53 and Sp1 was observed in TS. In NSCLC cells, high levels of active Notch1 can promote a reversible shift of driver dependence from EGFR to Notch1, leading to resistance to EGFR inhibitors.

scholarly journals Structure-based design of some quinazoline derivatives as epidermal growth factor receptor inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Muhammad Tukur Ibrahim ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Pharmacokinetic Profile ◽  
Egfr Inhibitors ◽  
Tyrosine Kinase Receptor ◽  
Egfr Tyrosine Kinase ◽  
Epidermal Growth

Abstract Background The discovery of epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer, most especially non-small cell lung cancer (NSCLC), was one of the major challenges encountered by the medicinal chemist in the world. The treatment of EGFR tyrosine kinase to manage NSCLCs becomes an urgent therapeutic necessity. NSCLC was the foremost cause of cancer mortality worldwide. Therefore, there is a need to develop more EGFR inhibitors due to the development of drug resistance by the mutation. This research is aimed at designing new EGFR inhibitors using a structure-based design approach. Structure-based drug design comprises several steps such as protein structure retrieval and preparation, ligand library preparation, docking, and structural modification on the best hit compound to design new ones. Result Molecular docking virtual screening on fifty sets of quinazoline derivatives/epidermal growth factor receptor inhibitors against their target protein (EGFR tyrosine kinase receptor PDB entry: 3IKA) and pharmacokinetic profile predictions were performed to identify hit compounds with promising affinities toward their target and good pharmacokinetic profiles. The hit compounds identified were compound 6 with a binding affinity of − 9.3 kcal/mol, compounds 5 and 8, each with a binding affinity of − 9.1 kcal/mol, respectively. The three hit compounds bound to EGFR tyrosine kinase receptor via four different types of interactions which include conventional hydrogen bond, carbon-hydrogen bond, electrostatic, and hydrophobic interactions, respectively. The best hit (compound 6) among the 3 hit compounds was retained as a template and used to design sixteen new EGFR inhibitors. The sixteen newly designed compounds were also docked into the active site of EGFR tyrosine kinase receptor to study their mode of interactions with the receptor. The binding affinities of these newly designed compounds range from − 9.5 kcal/mol to − 10.2 kcal/mol. The pharmacokinetic profile predictions of these newly designed compounds were further examined and found to be orally bioavailable with good absorption, low toxicity level, and permeable properties. Conclusion The sixteen newly designed EGFR inhibitors were found to have better binding affinities than the template used in the designing process and afatinib the positive control (an FDA approved EGFR inhibitor). None of these designed compounds was found to violate more than the permissible limit set by RO5. More so, the newly designed compounds were found to have good synthetic accessibility which indicates that these newly designed compounds can be easily synthesized in the laboratory.

scholarly journals Combating resistance to EGFR inhibitors

2018 ◽  
Vol 18 (1) ◽  
pp. 18-18
Author(s):  
Sarah Crunkhorn
Keyword(s):  
Egfr Inhibitors
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