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Benzoxaboroles—Novel Autotaxin Inhibitors

Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, on...

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Autores principales: Kraljić, Kristina, Jelić, Dubravko, Žiher, Dinko, Cvrtila, Adam, Dragojević, Snježana, Sinković, Verona, Mesić, Milan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804080/
https://www.ncbi.nlm.nih.gov/pubmed/31547058
http://dx.doi.org/10.3390/molecules24193419
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author Kraljić, Kristina
Jelić, Dubravko
Žiher, Dinko
Cvrtila, Adam
Dragojević, Snježana
Sinković, Verona
Mesić, Milan
author_facet Kraljić, Kristina
Jelić, Dubravko
Žiher, Dinko
Cvrtila, Adam
Dragojević, Snježana
Sinković, Verona
Mesić, Milan
author_sort Kraljić, Kristina
collection PubMed
description Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability).
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spelling pubmed-68040802019-11-18 Benzoxaboroles—Novel Autotaxin Inhibitors Kraljić, Kristina Jelić, Dubravko Žiher, Dinko Cvrtila, Adam Dragojević, Snježana Sinković, Verona Mesić, Milan Molecules Article Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability). MDPI 2019-09-20 /pmc/articles/PMC6804080/ /pubmed/31547058 http://dx.doi.org/10.3390/molecules24193419 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kraljić, Kristina
Jelić, Dubravko
Žiher, Dinko
Cvrtila, Adam
Dragojević, Snježana
Sinković, Verona
Mesić, Milan
Benzoxaboroles—Novel Autotaxin Inhibitors
title Benzoxaboroles—Novel Autotaxin Inhibitors
title_full Benzoxaboroles—Novel Autotaxin Inhibitors
title_fullStr Benzoxaboroles—Novel Autotaxin Inhibitors
title_full_unstemmed Benzoxaboroles—Novel Autotaxin Inhibitors
title_short Benzoxaboroles—Novel Autotaxin Inhibitors
title_sort benzoxaboroles—novel autotaxin inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804080/
https://www.ncbi.nlm.nih.gov/pubmed/31547058
http://dx.doi.org/10.3390/molecules24193419
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