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Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance
BACKGROUND: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy. METHODS: We generated drug-resistant cells...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817326/ https://www.ncbi.nlm.nih.gov/pubmed/24071597 http://dx.doi.org/10.1038/bjc.2013.584 |
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author | Kaliszczak, M Patel, H Kroll, S H B Carroll, L Smith, G Delaney, S Heathcote, D A Bondke, A Fuchter, M J Coombes, R C Barrett, A G M Ali, S Aboagye, E O |
author_facet | Kaliszczak, M Patel, H Kroll, S H B Carroll, L Smith, G Delaney, S Heathcote, D A Bondke, A Fuchter, M J Coombes, R C Barrett, A G M Ali, S Aboagye, E O |
author_sort | Kaliszczak, M |
collection | PubMed |
description | BACKGROUND: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy. METHODS: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy. RESULTS: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å(2)) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively. CONCLUSION: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer. |
format | Online Article Text |
id | pubmed-3817326 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-38173262014-10-29 Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance Kaliszczak, M Patel, H Kroll, S H B Carroll, L Smith, G Delaney, S Heathcote, D A Bondke, A Fuchter, M J Coombes, R C Barrett, A G M Ali, S Aboagye, E O Br J Cancer Translational Therapeutics BACKGROUND: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy. METHODS: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy. RESULTS: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å(2)) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively. CONCLUSION: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer. Nature Publishing Group 2013-10-29 2013-09-26 /pmc/articles/PMC3817326/ /pubmed/24071597 http://dx.doi.org/10.1038/bjc.2013.584 Text en Copyright © 2013 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Translational Therapeutics Kaliszczak, M Patel, H Kroll, S H B Carroll, L Smith, G Delaney, S Heathcote, D A Bondke, A Fuchter, M J Coombes, R C Barrett, A G M Ali, S Aboagye, E O Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance |
title | Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance |
title_full | Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance |
title_fullStr | Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance |
title_full_unstemmed | Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance |
title_short | Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance |
title_sort | development of a cyclin-dependent kinase inhibitor devoid of abc transporter-dependent drug resistance |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817326/ https://www.ncbi.nlm.nih.gov/pubmed/24071597 http://dx.doi.org/10.1038/bjc.2013.584 |
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