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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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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). |
format | Online Article Text |
id | pubmed-6804080 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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