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Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, i...

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Autores principales: Wang, Chao, Diez, Juan, Park, Hajeung, Becker-Pauly, Christoph, Fields, Gregg B., Spicer, Timothy P., Scampavia, Louis D., Minond, Dmitriy, Bannister, Thomas D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997411/
https://www.ncbi.nlm.nih.gov/pubmed/33673639
http://dx.doi.org/10.3390/ph14030197
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author Wang, Chao
Diez, Juan
Park, Hajeung
Becker-Pauly, Christoph
Fields, Gregg B.
Spicer, Timothy P.
Scampavia, Louis D.
Minond, Dmitriy
Bannister, Thomas D.
author_facet Wang, Chao
Diez, Juan
Park, Hajeung
Becker-Pauly, Christoph
Fields, Gregg B.
Spicer, Timothy P.
Scampavia, Louis D.
Minond, Dmitriy
Bannister, Thomas D.
author_sort Wang, Chao
collection PubMed
description Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). Here, in part II, we report further efforts to optimize potency and selectivity. We hope that a hydroxamic acid meprin α inhibitor probe will help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.
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spelling pubmed-79974112021-03-27 Discovery and Optimization of Selective Inhibitors of Meprin α (Part II) Wang, Chao Diez, Juan Park, Hajeung Becker-Pauly, Christoph Fields, Gregg B. Spicer, Timothy P. Scampavia, Louis D. Minond, Dmitriy Bannister, Thomas D. Pharmaceuticals (Basel) Article Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). Here, in part II, we report further efforts to optimize potency and selectivity. We hope that a hydroxamic acid meprin α inhibitor probe will help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition. MDPI 2021-02-27 /pmc/articles/PMC7997411/ /pubmed/33673639 http://dx.doi.org/10.3390/ph14030197 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 (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Wang, Chao
Diez, Juan
Park, Hajeung
Becker-Pauly, Christoph
Fields, Gregg B.
Spicer, Timothy P.
Scampavia, Louis D.
Minond, Dmitriy
Bannister, Thomas D.
Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)
title Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)
title_full Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)
title_fullStr Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)
title_full_unstemmed Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)
title_short Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)
title_sort discovery and optimization of selective inhibitors of meprin α (part ii)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997411/
https://www.ncbi.nlm.nih.gov/pubmed/33673639
http://dx.doi.org/10.3390/ph14030197
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