Cargando…
Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2
Protein kinase CK2 is a highly pleiotropic protein kinase capable of phosphorylating hundreds of protein substrates. It is involved in numerous cellular functions, including cell viability, apoptosis, cell proliferation and survival, angiogenesis, or ER-stress response. As CK2 activity is found pert...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198750/ https://www.ncbi.nlm.nih.gov/pubmed/34070615 http://dx.doi.org/10.3390/molecules26113163 |
_version_ | 1783707213512048640 |
---|---|
author | Winiewska-Szajewska, Maria Maciejewska, Agnieszka Monika Speina, Elżbieta Poznański, Jarosław Paprocki, Daniel |
author_facet | Winiewska-Szajewska, Maria Maciejewska, Agnieszka Monika Speina, Elżbieta Poznański, Jarosław Paprocki, Daniel |
author_sort | Winiewska-Szajewska, Maria |
collection | PubMed |
description | Protein kinase CK2 is a highly pleiotropic protein kinase capable of phosphorylating hundreds of protein substrates. It is involved in numerous cellular functions, including cell viability, apoptosis, cell proliferation and survival, angiogenesis, or ER-stress response. As CK2 activity is found perturbed in many pathological states, including cancers, it becomes an attractive target for the pharma. A large number of low-mass ATP-competitive inhibitors have already been developed, the majority of them halogenated. We tested the binding of six series of halogenated heterocyclic ligands derived from the commercially available 4,5-dihalo-benzene-1,2-diamines. These ligand series were selected to enable the separation of the scaffold effect from the hydrophobic interactions attributed directly to the presence of halogen atoms. In silico molecular docking was initially applied to test the capability of each ligand for binding at the ATP-binding site of CK2. HPLC-derived ligand hydrophobicity data are compared with the binding affinity assessed by low-volume differential scanning fluorimetry (nanoDSF). We identified three promising ligand scaffolds, two of which have not yet been described as CK2 inhibitors but may lead to potent CK2 kinase inhibitors. The inhibitory activity against CK2α and toxicity against four reference cell lines have been determined for eight compounds identified as the most promising in nanoDSF assay. |
format | Online Article Text |
id | pubmed-8198750 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81987502021-06-14 Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2 Winiewska-Szajewska, Maria Maciejewska, Agnieszka Monika Speina, Elżbieta Poznański, Jarosław Paprocki, Daniel Molecules Article Protein kinase CK2 is a highly pleiotropic protein kinase capable of phosphorylating hundreds of protein substrates. It is involved in numerous cellular functions, including cell viability, apoptosis, cell proliferation and survival, angiogenesis, or ER-stress response. As CK2 activity is found perturbed in many pathological states, including cancers, it becomes an attractive target for the pharma. A large number of low-mass ATP-competitive inhibitors have already been developed, the majority of them halogenated. We tested the binding of six series of halogenated heterocyclic ligands derived from the commercially available 4,5-dihalo-benzene-1,2-diamines. These ligand series were selected to enable the separation of the scaffold effect from the hydrophobic interactions attributed directly to the presence of halogen atoms. In silico molecular docking was initially applied to test the capability of each ligand for binding at the ATP-binding site of CK2. HPLC-derived ligand hydrophobicity data are compared with the binding affinity assessed by low-volume differential scanning fluorimetry (nanoDSF). We identified three promising ligand scaffolds, two of which have not yet been described as CK2 inhibitors but may lead to potent CK2 kinase inhibitors. The inhibitory activity against CK2α and toxicity against four reference cell lines have been determined for eight compounds identified as the most promising in nanoDSF assay. MDPI 2021-05-25 /pmc/articles/PMC8198750/ /pubmed/34070615 http://dx.doi.org/10.3390/molecules26113163 Text en © 2021 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 Winiewska-Szajewska, Maria Maciejewska, Agnieszka Monika Speina, Elżbieta Poznański, Jarosław Paprocki, Daniel Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2 |
title | Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2 |
title_full | Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2 |
title_fullStr | Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2 |
title_full_unstemmed | Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2 |
title_short | Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2 |
title_sort | synthesis of novel halogenated heterocycles based on o-phenylenediamine and their interactions with the catalytic subunit of protein kinase ck2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198750/ https://www.ncbi.nlm.nih.gov/pubmed/34070615 http://dx.doi.org/10.3390/molecules26113163 |
work_keys_str_mv | AT winiewskaszajewskamaria synthesisofnovelhalogenatedheterocyclesbasedonophenylenediamineandtheirinteractionswiththecatalyticsubunitofproteinkinaseck2 AT maciejewskaagnieszkamonika synthesisofnovelhalogenatedheterocyclesbasedonophenylenediamineandtheirinteractionswiththecatalyticsubunitofproteinkinaseck2 AT speinaelzbieta synthesisofnovelhalogenatedheterocyclesbasedonophenylenediamineandtheirinteractionswiththecatalyticsubunitofproteinkinaseck2 AT poznanskijarosław synthesisofnovelhalogenatedheterocyclesbasedonophenylenediamineandtheirinteractionswiththecatalyticsubunitofproteinkinaseck2 AT paprockidaniel synthesisofnovelhalogenatedheterocyclesbasedonophenylenediamineandtheirinteractionswiththecatalyticsubunitofproteinkinaseck2 |