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Identification and Characterization of Novel CFTR Potentiators
There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the c...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212544/ https://www.ncbi.nlm.nih.gov/pubmed/30416447 http://dx.doi.org/10.3389/fphar.2018.01221 |
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author | Gees, Maarten Musch, Sara Van der Plas, Steven Wesse, Anne-Sophie Vandevelde, Ann Verdonck, Katleen Mammoliti, Oscar Hwang, Tzyh-Chang Sonck, Kathleen Stouten, Pieter Swensen, Andrew M. Jans, Mia Van der Schueren, Jan Nelles, Luc Andrews, Martin Conrath, Katja |
author_facet | Gees, Maarten Musch, Sara Van der Plas, Steven Wesse, Anne-Sophie Vandevelde, Ann Verdonck, Katleen Mammoliti, Oscar Hwang, Tzyh-Chang Sonck, Kathleen Stouten, Pieter Swensen, Andrew M. Jans, Mia Van der Schueren, Jan Nelles, Luc Andrews, Martin Conrath, Katja |
author_sort | Gees, Maarten |
collection | PubMed |
description | There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients. |
format | Online Article Text |
id | pubmed-6212544 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62125442018-11-09 Identification and Characterization of Novel CFTR Potentiators Gees, Maarten Musch, Sara Van der Plas, Steven Wesse, Anne-Sophie Vandevelde, Ann Verdonck, Katleen Mammoliti, Oscar Hwang, Tzyh-Chang Sonck, Kathleen Stouten, Pieter Swensen, Andrew M. Jans, Mia Van der Schueren, Jan Nelles, Luc Andrews, Martin Conrath, Katja Front Pharmacol Pharmacology There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients. Frontiers Media S.A. 2018-10-26 /pmc/articles/PMC6212544/ /pubmed/30416447 http://dx.doi.org/10.3389/fphar.2018.01221 Text en Copyright © 2018 Gees, Musch, Van der Plas, Wesse, Vandevelde, Verdonck, Mammoliti, Hwang, Sonck, Stouten, Swensen, Jans, Van der Schueren, Nelles, Andrews and Conrath. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Gees, Maarten Musch, Sara Van der Plas, Steven Wesse, Anne-Sophie Vandevelde, Ann Verdonck, Katleen Mammoliti, Oscar Hwang, Tzyh-Chang Sonck, Kathleen Stouten, Pieter Swensen, Andrew M. Jans, Mia Van der Schueren, Jan Nelles, Luc Andrews, Martin Conrath, Katja Identification and Characterization of Novel CFTR Potentiators |
title | Identification and Characterization of Novel CFTR Potentiators |
title_full | Identification and Characterization of Novel CFTR Potentiators |
title_fullStr | Identification and Characterization of Novel CFTR Potentiators |
title_full_unstemmed | Identification and Characterization of Novel CFTR Potentiators |
title_short | Identification and Characterization of Novel CFTR Potentiators |
title_sort | identification and characterization of novel cftr potentiators |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212544/ https://www.ncbi.nlm.nih.gov/pubmed/30416447 http://dx.doi.org/10.3389/fphar.2018.01221 |
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