[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-405903-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-405903-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","the-development-of-p53-targeted-therapies-for-human-cancers","The Development of p53-Targeted Therapies for Human Cancers","","p53 is a central tumor-suppressor and the most frequently mutated gene in human cancers. Many mutant forms (mutp53), especially missense variants, are expressed in tumors, while in cancers retaining wild-type p53 (wtp53) its activity is commonly reduced via mechanisms such as MDM2/MDMX-driven destabilization and inactivation. 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It is also the most frequently mutated gene in human cancers, making both wtp53 dysfunction and mutp53 activity relevant for therapy.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What mechanisms lead to p53 dysfunction in tumors?",{"text":68,"@type":64},"p53 dysfunction can arise from MDM2/MDMX-mediated destabilization and inactivation of wtp53, as well as from somatic p53 mutations. In tumors retaining wtp53, its activity is downregulated through multiple mechanisms.",{"name":70,"@type":61,"acceptedAnswer":71},"What therapeutic strategies are reviewed for p53-targeted cancer treatment?",{"text":72,"@type":64},"The review covers development of small molecules to disrupt the interaction between p53 and its negative regulators (MDM2/MDMX) in wtp53-expressing cancers, restore wtp53-like activity in mutp53-expressing cancers, and apply synthetic lethality approaches targeting pathways affected by p53 dysfunction.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},405903,1790901175,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,109,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":107,"slug":108},40,"healthcare",{"id":110,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},8,"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":55,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},1099523882367,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","cancers   \nReview  \nThe Development of p53-Targeted Therapies for Human Cancers  \nYier Lu 1,†, Meng Wu 1,†, Yang Xu 2,3,* and Lili Yu 1, *  \nCitation: Lu, Y.; Wu, M.; Xu, Y.; Yu, L. The Development of p53-Targeted Therapies for Human Cancers. Cancers 2023, 15, 3560. [https://](https://)[ ](https://)[doi.org/10.3390/cancers15143560](doi.org/10.3390/cancers15143560)  \nAcademic Editor: Patricia A.J. Muller  \nReceived: 3 June 2023  \nRevised: 27 June 2023  \nAccepted: 29 June 2023  \nPublished: 10 July 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; [22118554@zju.edu.cn](22118554@zju.edu.cn) (Y.L.); [12118327@zju.edu.cn](12118327@zju.edu.cn) (M.W.)  \n2 Department of Cardiology, The Second Affiliated Hospital, Cardiovascular Key Lab of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou 310009, China  \n3 Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA  \n* Correspondence: [xuyang2020@zju.edu.cn](xuyang2020@zju.edu.cn) (Y.X.); [2321128@zju.edu.cn](2321128@zju.edu.cn) (L.Y.)† These authors contributed equally to this work.  \nSimple Summary: Dysfunction of p53 has a significant impact on the resistance of tumor cells to various therapeutic agents. The major mechanisms causing p53 dysfunction include the MDM2/MDMXmediated destabilization and inactivation of wtp53 and somatic p53 mutations. Despite an intensive search for therapeutic strategies to induce wtp53-like activities in tumor cells, their clinical efficacyand safety remain tobe established. In this review, we summarize recent advances in the development of p53-targeting drugs, including their distinct mechanisms of action and potential in tumor therapy.  \nAbstract: p53 plays a critical role in tumor suppression and is the most frequently mutated gene in human cancers. Most p53 mutants (mutp53) are missense mutations and are thus expressed in human cancers. In human cancers that retain wtp53, the wtp53 activities are downregulated through multiple mechanisms. For example, the overexpression of the negative regulators of p53, MDM2/MDMX, can also efficiently destabilize and inactivate wtp53 . Therefore, both wtp53 and mutp53 have become promising and intensively explored therapeutic targets for cancer treatment. Current efforts include the development of small molecule compounds to disrupt the interaction between wtp53 and MDM2/MDMX in human cancers expressing wtp53 and to restore wtp53-like activity to p53 mutants in human cancers expressing mutp53 . In addition, a synthetic lethality approach has been applied to identify signaling pathways affected by p53 dysfunction, which, when targeted, can lead to cell death. While an intensive search for p53-targeted cancer therapy has produced potential candidates with encouraging preclinical efficacy data, it remains challenging to develop such drugs with good efficacy and safety profiles. A more in-depth understanding of the mechanisms of action of these p53-targeting drugs will help to overcome these challenges.  \nKeywords: p53 mutation; targeted therapy; gain-of-function; DNA-binding activity; MDM2/MDMX  \n1. Introduction  \nThe tumor suppressor p53 plays a critical role in tumor suppression by directly regulating the expression of hundreds of genes important for the cell cycle, apoptosis, senescence, differentiation, and metabolism of normal cells [1] . Therefore, to evade the powerful tumorsuppressive activities of wtp53, the p53 gene has become the ","cbCaijyhCw5C9hjy","https://ap.wps.com/l/cbCaijyhCw5C9hjy","pdf",475321,15,"English","# Simple Summary\n# Abstract\n# Keywords\n# 1. Introduction\n## Strategies for targeting p53 in human cancers","[{\"question\":\"Why is p53 considered a key therapeutic target in human cancers?\",\"answer\":\"p53 is a major tumor suppressor that regulates genes controlling the cell cycle, apoptosis, senescence, differentiation, and metabolism. It is also the most frequently mutated gene in human cancers, making both wtp53 dysfunction and mutp53 activity relevant for therapy.\"},{\"question\":\"What mechanisms lead to p53 dysfunction in tumors?\",\"answer\":\"p53 dysfunction can arise from MDM2/MDMX-mediated destabilization and inactivation of wtp53, as well as from somatic p53 mutations. In tumors retaining wtp53, its activity is downregulated through multiple mechanisms.\"},{\"question\":\"What therapeutic strategies are reviewed for p53-targeted cancer treatment?\",\"answer\":\"The review covers development of small molecules to disrupt the interaction between p53 and its negative regulators (MDM2/MDMX) in wtp53-expressing cancers, restore wtp53-like activity in mutp53-expressing cancers, and apply synthetic lethality approaches targeting pathways affected by p53 dysfunction.\"}]","The Development of p53-Targeted Therapies for Human Cancers | PDF",1790562471,38]