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Progress towards a clinically-successful ATR inhibitor for cancer therapy

The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment,...

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Autores principales: Barnieh, Francis M., Loadman, Paul M., Falconer, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663972/
https://www.ncbi.nlm.nih.gov/pubmed/34909652
http://dx.doi.org/10.1016/j.crphar.2021.100017
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author Barnieh, Francis M.
Loadman, Paul M.
Falconer, Robert A.
author_facet Barnieh, Francis M.
Loadman, Paul M.
Falconer, Robert A.
author_sort Barnieh, Francis M.
collection PubMed
description The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions.
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spelling pubmed-86639722021-12-13 Progress towards a clinically-successful ATR inhibitor for cancer therapy Barnieh, Francis M. Loadman, Paul M. Falconer, Robert A. Curr Res Pharmacol Drug Discov Review Article The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions. Elsevier 2021-02-05 /pmc/articles/PMC8663972/ /pubmed/34909652 http://dx.doi.org/10.1016/j.crphar.2021.100017 Text en Crown Copyright © 2021 Published by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Review Article
Barnieh, Francis M.
Loadman, Paul M.
Falconer, Robert A.
Progress towards a clinically-successful ATR inhibitor for cancer therapy
title Progress towards a clinically-successful ATR inhibitor for cancer therapy
title_full Progress towards a clinically-successful ATR inhibitor for cancer therapy
title_fullStr Progress towards a clinically-successful ATR inhibitor for cancer therapy
title_full_unstemmed Progress towards a clinically-successful ATR inhibitor for cancer therapy
title_short Progress towards a clinically-successful ATR inhibitor for cancer therapy
title_sort progress towards a clinically-successful atr inhibitor for cancer therapy
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663972/
https://www.ncbi.nlm.nih.gov/pubmed/34909652
http://dx.doi.org/10.1016/j.crphar.2021.100017
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