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Targeting intrinsically disordered proteins involved in cancer

Intrinsically disordered proteins (IDPs) do not have a well-defined structure under physiological conditions, but they have key roles in cell signaling and regulation, and they are frequently related to the development of diseases, such as cancer and other malignancies. This has converted IDPs in at...

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Autores principales: Santofimia-Castaño, Patricia, Rizzuti, Bruno, Xia, Yi, Abian, Olga, Peng, Ling, Velázquez-Campoy, Adrián, Neira, José L., Iovanna, Juan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190594/
https://www.ncbi.nlm.nih.gov/pubmed/31667555
http://dx.doi.org/10.1007/s00018-019-03347-3
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author Santofimia-Castaño, Patricia
Rizzuti, Bruno
Xia, Yi
Abian, Olga
Peng, Ling
Velázquez-Campoy, Adrián
Neira, José L.
Iovanna, Juan
author_facet Santofimia-Castaño, Patricia
Rizzuti, Bruno
Xia, Yi
Abian, Olga
Peng, Ling
Velázquez-Campoy, Adrián
Neira, José L.
Iovanna, Juan
author_sort Santofimia-Castaño, Patricia
collection PubMed
description Intrinsically disordered proteins (IDPs) do not have a well-defined structure under physiological conditions, but they have key roles in cell signaling and regulation, and they are frequently related to the development of diseases, such as cancer and other malignancies. This has converted IDPs in attractive therapeutic targets; however, targeting IDPs is challenging because of their dynamic nature. In the last years, different experimental and computational approaches, as well as the combination of both, have been explored to identify molecules to target either the hot-spots or the allosteric sites of IDPs. In this review, we summarize recent developments in successful targeting of IDPs, all of which are involved in different cancer types. The strategies used to develop and design (or in one particular example, to repurpose) small molecules targeting IDPs are, in a global sense, similar to those used in well-folded proteins: (1) screening of chemically diverse or target-oriented compound libraries; or (2) study of the interfaces involved in recognition of their natural partners, and design of molecular candidates capable of binding to such binding interface. We describe the outcomes of using these approaches in targeting IDPs involved in cancer, in the view to providing insight, to target IDPs in general. In a broad sense, the designed small molecules seem to target the most hydrophobic regions of the IDPs, hampering macromolecule (DNA or protein)–IDP interactions; furthermore, in most of the molecule–IDP complexes described so far, the protein remains disordered.
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spelling pubmed-71905942020-05-04 Targeting intrinsically disordered proteins involved in cancer Santofimia-Castaño, Patricia Rizzuti, Bruno Xia, Yi Abian, Olga Peng, Ling Velázquez-Campoy, Adrián Neira, José L. Iovanna, Juan Cell Mol Life Sci Review Intrinsically disordered proteins (IDPs) do not have a well-defined structure under physiological conditions, but they have key roles in cell signaling and regulation, and they are frequently related to the development of diseases, such as cancer and other malignancies. This has converted IDPs in attractive therapeutic targets; however, targeting IDPs is challenging because of their dynamic nature. In the last years, different experimental and computational approaches, as well as the combination of both, have been explored to identify molecules to target either the hot-spots or the allosteric sites of IDPs. In this review, we summarize recent developments in successful targeting of IDPs, all of which are involved in different cancer types. The strategies used to develop and design (or in one particular example, to repurpose) small molecules targeting IDPs are, in a global sense, similar to those used in well-folded proteins: (1) screening of chemically diverse or target-oriented compound libraries; or (2) study of the interfaces involved in recognition of their natural partners, and design of molecular candidates capable of binding to such binding interface. We describe the outcomes of using these approaches in targeting IDPs involved in cancer, in the view to providing insight, to target IDPs in general. In a broad sense, the designed small molecules seem to target the most hydrophobic regions of the IDPs, hampering macromolecule (DNA or protein)–IDP interactions; furthermore, in most of the molecule–IDP complexes described so far, the protein remains disordered. Springer International Publishing 2019-10-30 2020 /pmc/articles/PMC7190594/ /pubmed/31667555 http://dx.doi.org/10.1007/s00018-019-03347-3 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Review
Santofimia-Castaño, Patricia
Rizzuti, Bruno
Xia, Yi
Abian, Olga
Peng, Ling
Velázquez-Campoy, Adrián
Neira, José L.
Iovanna, Juan
Targeting intrinsically disordered proteins involved in cancer
title Targeting intrinsically disordered proteins involved in cancer
title_full Targeting intrinsically disordered proteins involved in cancer
title_fullStr Targeting intrinsically disordered proteins involved in cancer
title_full_unstemmed Targeting intrinsically disordered proteins involved in cancer
title_short Targeting intrinsically disordered proteins involved in cancer
title_sort targeting intrinsically disordered proteins involved in cancer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190594/
https://www.ncbi.nlm.nih.gov/pubmed/31667555
http://dx.doi.org/10.1007/s00018-019-03347-3
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