scholarly journals EGFR Signaling and its inhibition by EGFR inhibitors in NSCLC

2014 ◽  
Vol 2 (4) ◽  
pp. 375-388
Author(s):  
Rajvi Patel
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
The United States ◽  
Egfr Inhibitors ◽  
Growth And Survival ◽  
Over Expression ◽  
Epidermal Growth

Lung cancer is the third most cancer among the population. The American society’s estimation for lung cancer in the United States for 2014 states that about 2,24,210 people are suffering from the lung cancer and 1,59,260 deaths are occur from lung cancer. Among all the types of lung cancer, NSCLC (Non-Small cell Lung Cancer) represents 85% of the lung cancer. The estimated spread of NSCLC is 2,26,160 and 1,60,340 cases are of death in 2012. One of the risk factor for NSCLC is over expression of epidermal growth factor receptor (EGFR) and its intracellular signaling pathways. EGFR is over expressed in 40-80 % cases of NSCLC. EGFR belongs to the ErbB family of receptor tyrosinekinases (RTK) having molecular weight 170 to 185 kDa. Epidermal Growth Factor (EGF) binds to the EGFR at its extracellular domain and this binding leads to the homo or hetero dimerization and autophosphorylation of EGFR which initiates the several intracellular pathways. Several mutations in EGFR or in any of the proteins of the pathway leads to the growth and survival of the tumor cells. So in order to inhibit the growth of tumor cell, several EGFR inhibitors and targeted therapies are found to target the particular mutations.DOI: http://dx.doi.org/10.3126/ijasbt.v2i4.11263 Int J Appl Sci Biotechnol, Vol. 2(4): 375-388 

Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer

2018 ◽  
Vol 18 (8) ◽  
pp. 773-791
Author(s):  
Dhaval Sanchala ◽  
Lokesh K. Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Driver Mutations ◽  
Therapeutic Approaches ◽  
Epidermal Growth ◽  
Egfr Mutant

Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal Growth Factor Receptor (EGFR) is the most regular driver mutation encountered in Non-Small Cell Lung Cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma. This article presents a detailed molecular insight of the therapeutic approaches for the treatment of EGFR mutant lung cancer. The article delineates molecular mechanism of the drugs that are approved, the drugs that are in clinical trial and the drugs that have not entered a clinical trial but shows promising future in the treatment of EGFR mutant lung cancer. Furthermore, this article provides concise information on relevant combinational or monotherapy clinical trials that have been completed for various approaches.

scholarly journals Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

2021 ◽  
Vol 22 (5) ◽  
pp. 2625
Author(s):  
Sara Elena Rebuzzi ◽  
Lodovica Zullo ◽  
Giovanni Rossi ◽  
Massimiliano Grassi ◽  
Veronica Murianni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Molecular Targets ◽  
Small Cell ◽  
Targeted Agents ◽  
Small Cell Lung ◽  
Epidermal Growth

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

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.

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