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Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model

Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number...

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Autores principales: Vasilevich, Natalya I., Tatarskiy, Victor V., Aksenova, Elena A., Kazyulkin, Denis N., Afanasyev, Ilya I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932537/
https://www.ncbi.nlm.nih.gov/pubmed/27089349
http://dx.doi.org/10.3390/ph9020019
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author Vasilevich, Natalya I.
Tatarskiy, Victor V.
Aksenova, Elena A.
Kazyulkin, Denis N.
Afanasyev, Ilya I.
author_facet Vasilevich, Natalya I.
Tatarskiy, Victor V.
Aksenova, Elena A.
Kazyulkin, Denis N.
Afanasyev, Ilya I.
author_sort Vasilevich, Natalya I.
collection PubMed
description Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against Ser/Thr kinases such as Aurora A, Aurora B and Haspin. Our work on the optimization of these molecules against Aurora A kinase allowed us to achieve several hits in a 3–5 nM range of activity with rather good selectivity and Absorption, Distribution, Metabolism, and Excretion (ADME) properties, and cytotoxicity against 16 cancer cell lines. Thus, we showed the possibility to fine-tune the general Ser/Thr pharmacophore to design active and selective compounds against desired types of kinases.
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spelling pubmed-49325372016-07-13 Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model Vasilevich, Natalya I. Tatarskiy, Victor V. Aksenova, Elena A. Kazyulkin, Denis N. Afanasyev, Ilya I. Pharmaceuticals (Basel) Article Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against Ser/Thr kinases such as Aurora A, Aurora B and Haspin. Our work on the optimization of these molecules against Aurora A kinase allowed us to achieve several hits in a 3–5 nM range of activity with rather good selectivity and Absorption, Distribution, Metabolism, and Excretion (ADME) properties, and cytotoxicity against 16 cancer cell lines. Thus, we showed the possibility to fine-tune the general Ser/Thr pharmacophore to design active and selective compounds against desired types of kinases. MDPI 2016-04-13 /pmc/articles/PMC4932537/ /pubmed/27089349 http://dx.doi.org/10.3390/ph9020019 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vasilevich, Natalya I.
Tatarskiy, Victor V.
Aksenova, Elena A.
Kazyulkin, Denis N.
Afanasyev, Ilya I.
Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model
title Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model
title_full Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model
title_fullStr Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model
title_full_unstemmed Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model
title_short Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model
title_sort search for potent and selective aurora a inhibitors based on general ser/thr kinase pharmacophore model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932537/
https://www.ncbi.nlm.nih.gov/pubmed/27089349
http://dx.doi.org/10.3390/ph9020019
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