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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
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.
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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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