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Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6
Kallikrein‐related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004151/ https://www.ncbi.nlm.nih.gov/pubmed/31675166 http://dx.doi.org/10.1002/cmdc.201900536 |
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author | De Vita, Elena Smits, Niels van den Hurk, Helma Beck, Elizabeth M. Hewitt, Joanne Baillie, Gemma Russell, Emily Pannifer, Andrew Hamon, Véronique Morrison, Angus McElroy, Stuart P. Jones, Philip Ignatenko, Natalia A. Gunkel, Nikolas Miller, Aubry K. |
author_facet | De Vita, Elena Smits, Niels van den Hurk, Helma Beck, Elizabeth M. Hewitt, Joanne Baillie, Gemma Russell, Emily Pannifer, Andrew Hamon, Véronique Morrison, Angus McElroy, Stuart P. Jones, Philip Ignatenko, Natalia A. Gunkel, Nikolas Miller, Aubry K. |
author_sort | De Vita, Elena |
collection | PubMed |
description | Kallikrein‐related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high‐throughput screen within the European Lead Factory program. Structure‐guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)‐3‐(4‐carbamimidoylphenyl)‐N‐((S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) and 34 ((5R)‐3‐(6‐carbamimidoylpyridin‐3‐yl)‐N‐((1S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) have single‐digit nanomolar potency against KLK6, with over 25‐fold and 100‐fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6‐dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo. |
format | Online Article Text |
id | pubmed-7004151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70041512020-02-11 Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6 De Vita, Elena Smits, Niels van den Hurk, Helma Beck, Elizabeth M. Hewitt, Joanne Baillie, Gemma Russell, Emily Pannifer, Andrew Hamon, Véronique Morrison, Angus McElroy, Stuart P. Jones, Philip Ignatenko, Natalia A. Gunkel, Nikolas Miller, Aubry K. ChemMedChem Full Papers Kallikrein‐related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high‐throughput screen within the European Lead Factory program. Structure‐guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)‐3‐(4‐carbamimidoylphenyl)‐N‐((S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) and 34 ((5R)‐3‐(6‐carbamimidoylpyridin‐3‐yl)‐N‐((1S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) have single‐digit nanomolar potency against KLK6, with over 25‐fold and 100‐fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6‐dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo. John Wiley and Sons Inc. 2019-11-18 2020-01-07 /pmc/articles/PMC7004151/ /pubmed/31675166 http://dx.doi.org/10.1002/cmdc.201900536 Text en ©2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Full Papers De Vita, Elena Smits, Niels van den Hurk, Helma Beck, Elizabeth M. Hewitt, Joanne Baillie, Gemma Russell, Emily Pannifer, Andrew Hamon, Véronique Morrison, Angus McElroy, Stuart P. Jones, Philip Ignatenko, Natalia A. Gunkel, Nikolas Miller, Aubry K. Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6 |
title | Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6 |
title_full | Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6 |
title_fullStr | Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6 |
title_full_unstemmed | Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6 |
title_short | Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6 |
title_sort | synthesis and structure‐activity relationships of n‐(4‐benzamidino)‐oxazolidinones: potent and selective inhibitors of kallikrein‐related peptidase 6 |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004151/ https://www.ncbi.nlm.nih.gov/pubmed/31675166 http://dx.doi.org/10.1002/cmdc.201900536 |
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