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Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study

Targeting L858R/T790M and L858R/T790M/C797S mutant EGFR is a critical challenge in developing EGFR tyrosine kinase inhibitors to overcome drug resistance in non-small cell lung cancer (NSCLC). The discovery of next-generation EGFR tyrosine kinase inhibitors (TKIs) is therefore necessary. To this end...

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Autores principales: Todsaporn, Duangjai, Zubenko, Alexander, Kartsev, Victor, Aiebchun, Thitinan, Mahalapbutr, Panupong, Petrou, Anthi, Geronikaki, Athina, Divaeva, Liudmila, Chekrisheva, Victoria, Yildiz, Ilkay, Choowongkomon, Kiattawee, Rungrotmongkol, Thanyada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10096398/
https://www.ncbi.nlm.nih.gov/pubmed/37049777
http://dx.doi.org/10.3390/molecules28073014
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author Todsaporn, Duangjai
Zubenko, Alexander
Kartsev, Victor
Aiebchun, Thitinan
Mahalapbutr, Panupong
Petrou, Anthi
Geronikaki, Athina
Divaeva, Liudmila
Chekrisheva, Victoria
Yildiz, Ilkay
Choowongkomon, Kiattawee
Rungrotmongkol, Thanyada
author_facet Todsaporn, Duangjai
Zubenko, Alexander
Kartsev, Victor
Aiebchun, Thitinan
Mahalapbutr, Panupong
Petrou, Anthi
Geronikaki, Athina
Divaeva, Liudmila
Chekrisheva, Victoria
Yildiz, Ilkay
Choowongkomon, Kiattawee
Rungrotmongkol, Thanyada
author_sort Todsaporn, Duangjai
collection PubMed
description Targeting L858R/T790M and L858R/T790M/C797S mutant EGFR is a critical challenge in developing EGFR tyrosine kinase inhibitors to overcome drug resistance in non-small cell lung cancer (NSCLC). The discovery of next-generation EGFR tyrosine kinase inhibitors (TKIs) is therefore necessary. To this end, a series of furopyridine derivatives were evaluated for their EGFR-based inhibition and antiproliferative activities using computational and biological approaches. We found that several compounds derived from virtual screening based on a molecular docking and solvated interaction energy (SIE) method showed the potential to suppress wild-type and mutant EGFR. The most promising PD13 displayed strong inhibitory activity against wild-type (IC(50) of 11.64 ± 1.30 nM), L858R/T790M (IC(50) of 10.51 ± 0.71 nM), which are more significant than known drugs. In addition, PD13 revealed a potent cytotoxic effect on A549 and H1975 cell lines with IC(50) values of 18.09 ± 1.57 and 33.87 ± 0.86 µM, respectively. The 500-ns MD simulations indicated that PD13 formed a hydrogen bond with Met793 at the hinge region, thus creating excellent EGFR inhibitory activity. Moreover, the binding of PD13 in the hinge region of EGFR was the major determining factor in stabilizing the interactions via hydrogen bonds and van der Waals (vdW). Altogether, PD13 is a promising novel EGFR inhibitor that could be further clinically developed as fourth-generation EGFR-TKIs.
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spelling pubmed-100963982023-04-13 Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study Todsaporn, Duangjai Zubenko, Alexander Kartsev, Victor Aiebchun, Thitinan Mahalapbutr, Panupong Petrou, Anthi Geronikaki, Athina Divaeva, Liudmila Chekrisheva, Victoria Yildiz, Ilkay Choowongkomon, Kiattawee Rungrotmongkol, Thanyada Molecules Article Targeting L858R/T790M and L858R/T790M/C797S mutant EGFR is a critical challenge in developing EGFR tyrosine kinase inhibitors to overcome drug resistance in non-small cell lung cancer (NSCLC). The discovery of next-generation EGFR tyrosine kinase inhibitors (TKIs) is therefore necessary. To this end, a series of furopyridine derivatives were evaluated for their EGFR-based inhibition and antiproliferative activities using computational and biological approaches. We found that several compounds derived from virtual screening based on a molecular docking and solvated interaction energy (SIE) method showed the potential to suppress wild-type and mutant EGFR. The most promising PD13 displayed strong inhibitory activity against wild-type (IC(50) of 11.64 ± 1.30 nM), L858R/T790M (IC(50) of 10.51 ± 0.71 nM), which are more significant than known drugs. In addition, PD13 revealed a potent cytotoxic effect on A549 and H1975 cell lines with IC(50) values of 18.09 ± 1.57 and 33.87 ± 0.86 µM, respectively. The 500-ns MD simulations indicated that PD13 formed a hydrogen bond with Met793 at the hinge region, thus creating excellent EGFR inhibitory activity. Moreover, the binding of PD13 in the hinge region of EGFR was the major determining factor in stabilizing the interactions via hydrogen bonds and van der Waals (vdW). Altogether, PD13 is a promising novel EGFR inhibitor that could be further clinically developed as fourth-generation EGFR-TKIs. MDPI 2023-03-28 /pmc/articles/PMC10096398/ /pubmed/37049777 http://dx.doi.org/10.3390/molecules28073014 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Todsaporn, Duangjai
Zubenko, Alexander
Kartsev, Victor
Aiebchun, Thitinan
Mahalapbutr, Panupong
Petrou, Anthi
Geronikaki, Athina
Divaeva, Liudmila
Chekrisheva, Victoria
Yildiz, Ilkay
Choowongkomon, Kiattawee
Rungrotmongkol, Thanyada
Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study
title Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study
title_full Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study
title_fullStr Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study
title_full_unstemmed Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study
title_short Discovery of Novel EGFR Inhibitor Targeting Wild-Type and Mutant Forms of EGFR: In Silico and In Vitro Study
title_sort discovery of novel egfr inhibitor targeting wild-type and mutant forms of egfr: in silico and in vitro study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10096398/
https://www.ncbi.nlm.nih.gov/pubmed/37049777
http://dx.doi.org/10.3390/molecules28073014
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