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The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma
CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC(50) was 1.4nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC(50) 30-220nM) and enhanced gemcitabi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823038/ https://www.ncbi.nlm.nih.gov/pubmed/26295308 http://dx.doi.org/10.18632/oncotarget.4919 |
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author | Walton, Mike I. Eve, Paul D. Hayes, Angela Henley, Alan T. Valenti, Melanie R. De Haven Brandon, Alexis K. Box, Gary Boxall, Kathy J. Tall, Matthew Swales, Karen Matthews, Thomas P. McHardy, Tatiana Lainchbury, Michael Osborne, James Hunter, Jill E. Perkins, Neil D. Aherne, G. Wynne Reader, John C. Raynaud, Florence I. Eccles, Suzanne A. Collins, Ian Garrett, Michelle D. |
author_facet | Walton, Mike I. Eve, Paul D. Hayes, Angela Henley, Alan T. Valenti, Melanie R. De Haven Brandon, Alexis K. Box, Gary Boxall, Kathy J. Tall, Matthew Swales, Karen Matthews, Thomas P. McHardy, Tatiana Lainchbury, Michael Osborne, James Hunter, Jill E. Perkins, Neil D. Aherne, G. Wynne Reader, John C. Raynaud, Florence I. Eccles, Suzanne A. Collins, Ian Garrett, Michelle D. |
author_sort | Walton, Mike I. |
collection | PubMed |
description | CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC(50) was 1.4nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC(50) 30-220nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition. |
format | Online Article Text |
id | pubmed-4823038 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-48230382016-05-03 The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma Walton, Mike I. Eve, Paul D. Hayes, Angela Henley, Alan T. Valenti, Melanie R. De Haven Brandon, Alexis K. Box, Gary Boxall, Kathy J. Tall, Matthew Swales, Karen Matthews, Thomas P. McHardy, Tatiana Lainchbury, Michael Osborne, James Hunter, Jill E. Perkins, Neil D. Aherne, G. Wynne Reader, John C. Raynaud, Florence I. Eccles, Suzanne A. Collins, Ian Garrett, Michelle D. Oncotarget Research Paper CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC(50) was 1.4nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC(50) 30-220nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition. Impact Journals LLC 2015-07-22 /pmc/articles/PMC4823038/ /pubmed/26295308 http://dx.doi.org/10.18632/oncotarget.4919 Text en Copyright: © 2016 Walton et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Walton, Mike I. Eve, Paul D. Hayes, Angela Henley, Alan T. Valenti, Melanie R. De Haven Brandon, Alexis K. Box, Gary Boxall, Kathy J. Tall, Matthew Swales, Karen Matthews, Thomas P. McHardy, Tatiana Lainchbury, Michael Osborne, James Hunter, Jill E. Perkins, Neil D. Aherne, G. Wynne Reader, John C. Raynaud, Florence I. Eccles, Suzanne A. Collins, Ian Garrett, Michelle D. The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma |
title | The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma |
title_full | The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma |
title_fullStr | The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma |
title_full_unstemmed | The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma |
title_short | The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma |
title_sort | clinical development candidate cct245737 is an orally active chk1 inhibitor with preclinical activity in ras mutant nsclc and eμ-myc driven b-cell lymphoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823038/ https://www.ncbi.nlm.nih.gov/pubmed/26295308 http://dx.doi.org/10.18632/oncotarget.4919 |
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