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Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade
RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activa...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
F1000Research
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937820/ https://www.ncbi.nlm.nih.gov/pubmed/27429741 http://dx.doi.org/10.12688/f1000research.8724.2 |
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author | Watson, Amanda J. Hopkins, Gemma V. Hitchin, Samantha Begum, Habiba Jones, Stuart Jordan, Allan Holt, Sarah March, H. Nikki Newton, Rebecca Small, Helen Stowell, Alex Waddell, Ian D. Waszkowycz, Bohdan Ogilvie, Donald J. |
author_facet | Watson, Amanda J. Hopkins, Gemma V. Hitchin, Samantha Begum, Habiba Jones, Stuart Jordan, Allan Holt, Sarah March, H. Nikki Newton, Rebecca Small, Helen Stowell, Alex Waddell, Ian D. Waszkowycz, Bohdan Ogilvie, Donald J. |
author_sort | Watson, Amanda J. |
collection | PubMed |
description | RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series. Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile. |
format | Online Article Text |
id | pubmed-4937820 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | F1000Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-49378202016-07-15 Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade Watson, Amanda J. Hopkins, Gemma V. Hitchin, Samantha Begum, Habiba Jones, Stuart Jordan, Allan Holt, Sarah March, H. Nikki Newton, Rebecca Small, Helen Stowell, Alex Waddell, Ian D. Waszkowycz, Bohdan Ogilvie, Donald J. F1000Res Research Article RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series. Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile. F1000Research 2016-08-23 /pmc/articles/PMC4937820/ /pubmed/27429741 http://dx.doi.org/10.12688/f1000research.8724.2 Text en Copyright: © 2016 Watson AJ et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Watson, Amanda J. Hopkins, Gemma V. Hitchin, Samantha Begum, Habiba Jones, Stuart Jordan, Allan Holt, Sarah March, H. Nikki Newton, Rebecca Small, Helen Stowell, Alex Waddell, Ian D. Waszkowycz, Bohdan Ogilvie, Donald J. Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade |
title | Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade |
title_full | Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade |
title_fullStr | Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade |
title_full_unstemmed | Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade |
title_short | Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade |
title_sort | identification of selective inhibitors of ret and comparison with current clinical candidates through development and validation of a robust screening cascade |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937820/ https://www.ncbi.nlm.nih.gov/pubmed/27429741 http://dx.doi.org/10.12688/f1000research.8724.2 |
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