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Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

p53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53–MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation....

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Autores principales: Zhu, Haohao, Gao, Hui, Ji, Yingying, Zhou, Qin, Du, Zhiqiang, Tian, Lin, Jiang, Ying, Yao, Kun, Zhou, Zhenhe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9277894/
https://www.ncbi.nlm.nih.gov/pubmed/35831864
http://dx.doi.org/10.1186/s13045-022-01314-3
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author Zhu, Haohao
Gao, Hui
Ji, Yingying
Zhou, Qin
Du, Zhiqiang
Tian, Lin
Jiang, Ying
Yao, Kun
Zhou, Zhenhe
author_facet Zhu, Haohao
Gao, Hui
Ji, Yingying
Zhou, Qin
Du, Zhiqiang
Tian, Lin
Jiang, Ying
Yao, Kun
Zhou, Zhenhe
author_sort Zhu, Haohao
collection PubMed
description p53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53–MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation. Blocking MDM2 to restore p53 function is a hotspot in the development of anticancer candidates. Till now, nine MDM2 inhibitors with different structural types have entered clinical trials. However, no MDM2 inhibitor has been approved for clinical application. This review focused on the discovery, structural modification, preclinical and clinical research of the above compounds from the perspective of medicinal chemistry. Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53–MDM2 interaction.
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spelling pubmed-92778942022-07-14 Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials Zhu, Haohao Gao, Hui Ji, Yingying Zhou, Qin Du, Zhiqiang Tian, Lin Jiang, Ying Yao, Kun Zhou, Zhenhe J Hematol Oncol Review p53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53–MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation. Blocking MDM2 to restore p53 function is a hotspot in the development of anticancer candidates. Till now, nine MDM2 inhibitors with different structural types have entered clinical trials. However, no MDM2 inhibitor has been approved for clinical application. This review focused on the discovery, structural modification, preclinical and clinical research of the above compounds from the perspective of medicinal chemistry. Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53–MDM2 interaction. BioMed Central 2022-07-13 /pmc/articles/PMC9277894/ /pubmed/35831864 http://dx.doi.org/10.1186/s13045-022-01314-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Review
Zhu, Haohao
Gao, Hui
Ji, Yingying
Zhou, Qin
Du, Zhiqiang
Tian, Lin
Jiang, Ying
Yao, Kun
Zhou, Zhenhe
Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials
title Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials
title_full Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials
title_fullStr Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials
title_full_unstemmed Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials
title_short Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials
title_sort targeting p53–mdm2 interaction by small-molecule inhibitors: learning from mdm2 inhibitors in clinical trials
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9277894/
https://www.ncbi.nlm.nih.gov/pubmed/35831864
http://dx.doi.org/10.1186/s13045-022-01314-3
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