Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study

The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Enco...

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Autores principales: Camposa, Ludmila E., Garibotto, Francisco, Angelina, Emilio Luis, Kos, Jiri, Gonec, Tomas, Marvanova, Pavlina, Vettorazzi, Marcela Cristina, Oravece, Michal, Jendrzejewska, Izabela, Jampilekc, Josef, Alvareza, Sergio E., Enriz, Ricardo D.
Formato: Artículo
Lenguaje:Inglés
Publicado: Elsevier 2025
Materias:
BRAF inhibitors
Melanoma
Molecular modeling
Cell viability
ERK phosphorylation
Acceso en línea:http://repositorio.unne.edu.ar/handle/123456789/56480
Aporte de:
RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) de Universidad Nacional del Nordeste
id I48-R184-123456789-56480
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spelling I48-R184-123456789-564802025-03-11T16:06:16Z Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study Camposa, Ludmila E. Garibotto, Francisco Angelina, Emilio Luis Kos, Jiri Gonec, Tomas Marvanova, Pavlina Vettorazzi, Marcela Cristina Oravece, Michal Jendrzejewska, Izabela Jampilekc, Josef Alvareza, Sergio E. Enriz, Ricardo D. BRAF inhibitors Melanoma Molecular modeling Cell viability ERK phosphorylation The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold. 2025-03-11T14:31:11Z 2025-03-11T14:31:11Z 2020-07-24 Artículo Camposa, Ludmila E., et al., 2020. Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study. Bioorganic Chemistry. Estados Unidos: Elsevier, vol. 103, p. 1-13. ISSN 0045-2068. 0045-2068 http://repositorio.unne.edu.ar/handle/123456789/56480 eng https://doi.org/10.1016/j.bioorg.2020.104145 openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ application/pdf p. 1-13 application/pdf Elsevier Bioorganic Chemistry, 2020, vol. 103, p. 1-13.
institution Universidad Nacional del Nordeste
institution_str I-48
repository_str R-184
collection RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE)
language Inglés
topic BRAF inhibitors
Melanoma
Molecular modeling
Cell viability
ERK phosphorylation
spellingShingle BRAF inhibitors
Melanoma
Molecular modeling
Cell viability
ERK phosphorylation
Camposa, Ludmila E.
Garibotto, Francisco
Angelina, Emilio Luis
Kos, Jiri
Gonec, Tomas
Marvanova, Pavlina
Vettorazzi, Marcela Cristina
Oravece, Michal
Jendrzejewska, Izabela
Jampilekc, Josef
Alvareza, Sergio E.
Enriz, Ricardo D.
Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
topic_facet BRAF inhibitors
Melanoma
Molecular modeling
Cell viability
ERK phosphorylation
description The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in several human cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA for the treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although many protocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness because patients invariably develop resistance and secondary toxic effects associated with the therapy. These limitations highlight the importance of designing new and better inhibitors with different structures that could establish different interactions in the active site of the enzyme and therefore decrease resistance progress. Considering the data from our previous report, here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, by establishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results we synthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold.
format Artículo
author Camposa, Ludmila E.
Garibotto, Francisco
Angelina, Emilio Luis
Kos, Jiri
Gonec, Tomas
Marvanova, Pavlina
Vettorazzi, Marcela Cristina
Oravece, Michal
Jendrzejewska, Izabela
Jampilekc, Josef
Alvareza, Sergio E.
Enriz, Ricardo D.
author_facet Camposa, Ludmila E.
Garibotto, Francisco
Angelina, Emilio Luis
Kos, Jiri
Gonec, Tomas
Marvanova, Pavlina
Vettorazzi, Marcela Cristina
Oravece, Michal
Jendrzejewska, Izabela
Jampilekc, Josef
Alvareza, Sergio E.
Enriz, Ricardo D.
author_sort Camposa, Ludmila E.
title Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
title_short Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
title_full Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
title_fullStr Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
title_full_unstemmed Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study
title_sort hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of braf inhibitors. a theoretical and experimental study
publisher Elsevier
publishDate 2025
url http://repositorio.unne.edu.ar/handle/123456789/56480
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