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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Structure-Based Virtual Screening for Defeating Drug Resistant Form of EGFR Protein
Amirhossein Sharifi, Kowsar Bagherzadeh, Sahand Golestanian
1Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran. amanlou@tums.ac.ir.
Abstract:
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 resolve the problem, a step-by-step rational virtual screening was employed over almost sixty million compounds of PubChem Compound Database to filter out selective inhibitor(s) of T790M/L858R subtype. Consequently, the compound CID 133077 was observed, an active metabolite of Axitirome and also a cholesterol lowering prodrug. Selecting this compound can be explained by the oxamic acid part of molecule. Hence, administration of Axitirome or other compounds which contain oxamic acid is suggested in cases with EGFR T790M/L858R drug resistance.
Insights
New research identifies a selective inhibitor for drug-resistant lung cancer mutations. This compound, CID 133077, targets specific epidermal growth factor receptor (EGFR) alterations, offering a potential solution for treatment resistance.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Epidermal growth factor receptor (EGFR) is crucial for cell regulation.
- Specific EGFR mutations (T790M/L858R) cause resistance to first-generation inhibitors.
- Second-generation inhibitors cause severe side effects due to broad-spectrum activity.
Purpose of the Study:
- To identify selective inhibitors for EGFR T790M/L858R mutations.
- To overcome treatment resistance in lung cancer.
- To find inhibitors with reduced side effects.
Main Methods:
- Rational virtual screening of PubChem Compound Database (approx. 60 million compounds).
- Identification of selective inhibitors for the T790M/L858R subtype.
- Analysis of compound structures for inhibitory potential.
Main Results:
- CID 133077, an Axitirome metabolite and cholesterol-lowering prodrug, was identified.
- The oxamic acid moiety in CID 133077 is key to its inhibitory activity.
- This compound shows selectivity for the T790M/L858R EGFR subtype.
Conclusions:
- CID 133077 is a promising candidate for treating EGFR T790M/L858R-mutated lung cancer.
- Axitirome or other oxamic acid-containing compounds are suggested for EGFR-resistant lung cancer.
- This finding offers a new therapeutic strategy for resistant lung cancer.
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