[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-369025-105":59,"doc-detail-369025-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","a-triple-action-protac-for-wild-type-p53-cancer-therapy","A triple-action PROTAC for wild-type p53 cancer therapy","","Triple-action proteolysis targeting chimera (TAPTAC) technology is introduced to reactivate apoptosis in wild-type p53 cancers by simultaneously engaging three oncogenic mechanisms. TAPTAC1 reprograms HDM2 to avoid p53 degradation while using HDM2 to eliminate oncogenic BET proteins, and it blocks HDMX-mediated sequestration to maximize p53 reactivation alongside targeted protein degradation. TAPTAC1 shows superior performance versus regimens lacking HDMX inhibition and is broadly effective across wild-type p53 cancer models while leveraging HDM2 dependency for improved selectivity and reduced toxicity.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-triple-action-protac-for-wild-type-p53-cancer-therapy/369025/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-triple-action-protac-for-wild-type-p53-cancer-therapy/369025.png","ImageObject",300,407,{"name":92,"@type":93},"LangkahRina","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is TAPTAC1 and how does it work in wild-type p53 cancers?","Question",{"text":113,"@type":114},"TAPTAC1 is a triple-action PROTAC that reactivates apoptosis in wild-type p53 cancers. It inhibits HDM2 and HDMX to maximize p53 reactivation while using HDM2 to degrade oncogenic BET proteins.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which targets does TAPTAC1 affect to achieve its therapeutic effect?",{"text":118,"@type":114},"TAPTAC1 targets HDM2 and HDMX to reprogram p53 signaling and also degrades oncogenic BET proteins. It achieves p53 reactivation alongside targeted protein degradation.",{"name":120,"@type":111,"acceptedAnswer":121},"Why is TAPTAC1 described as broadly effective and potentially safer than some prior approaches?",{"text":122,"@type":114},"TAPTAC1 is broadly effective against wild-type p53 cancers, including mouse models, while sparing normal cells. It leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},369025,1790928643,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},962090893776,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Article  \nA triple-action PROTAC for wild-type p53 cancer therapy  \nGraphical abstract  \nHDM2  \nHDMX  \nOncoprotein Degradation  \nBRD4  \np53  \np53  \nAnti-Tumor Activity  \nUbiquitination  \nE2  \nTAPTAC1  \np53 Reactivation  \nHighlights  \n• TAPTAC1 is a triple-action PROTAC that reactivates apoptosis in WT-p53 cancers  \nAuthors  \nGregory H. Bird, Utsarga Adhikary, Michael J. Schmidt,   ,  \nMichael D. Cameron, Steven P. Gygi, Loren D. Walensky  \nCorrespondence  \n[loren_walensky@dfci.harvard.edu](loren_walensky@dfci.harvard.edu)  \nIn brief  \nBird [et al. report](et al. report) that TAPTAC1, a tripleaction PROTAC, inhibits HDM2 and HDMX to maximally reactivate p53 while hijacking HDM2 to degrade oncogenic BET proteins. TAPTAC1 achieves potent, multiagent activity in WT-p53 cancers asa single drug, overcoming the in vivo efficacy and toxicity limitations of prior agents.  \n• By reprogramming HDM2, TAPTAC1 induces p53 activation and target degradation  \n• TAPTAC1 outperforms treatments that lack HDMX inhibitory activity  \n• TAPTAC1 is broadly effective against WT-p53 cancers, sparing normal cells  \nBird et al., 2025, Cell Reports Medicine 6, 102467  \nDecember 16, 2025 © 2025 The Author(s) . Published by Elsevier Inc.  \n[https://doi.org/10.1016/j.xcrm.2025.102467](https://doi.org/10.1016/j.xcrm.2025.102467)  \nll  \nll  \nOPEN ACCESS  \nArticle  \nA triple-action PROTAC  \nfor wild-type p53 cancer therapy  \nGregory H. Bird,1,7 Utsarga Adhikary,1,7 Michael J. Schmidt,1 Marina Godes,1 Bethany Tesar,1 Christina M. Camara,1 Joao A. Paulo,2 Julia F. Vidlak,1 Thomas M. DeAngelo,1 Marilyn Marquez,3 Prafulla Gokhale,3 Ruitong Li,4  \nShannan J. Ho Sui,5 Michael D. Cameron,6 Steven P. Gygi,2 and Loren D. Walensky1,8,*  \n1Department of Pediatric Oncology and Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA 02215, USA  \n2Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA  \n3Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02215, USA  \n4Broad Institute, Cambridge, MA 02142, USA  \n5Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, MA, USA  \n6Department of Molecular Medicine, University of Florida Scripps Institute, Jupiter, FL 33458, USA  \n7These authors contributed equally  \n8Lead contact  \n*Correspondence: [loren_walensky@dfci.harvard.edu](loren_walensky@dfci.harvard.edu)[ ](loren_walensky@dfci.harvard.edu)[https://doi.org/10.1016/j.xcrm.2025.102467](https://doi.org/10.1016/j.xcrm.2025.102467)  \nSUMMARY  \nDespite the central role of p53 suppression in cancer pathogenesis, the promise of therapeutic p53 reactivation remains unrealized, with targeted and combination chemotherapies limited by efficacy, toxicity, and delivery. To overcome these challenges, we introduce a triple-action proteolysis targeting chimera (TAPTAC) that simultaneously targets three oncogenic mechanisms to reactivate apoptosis. TAPTAC1 diverts HDM2 from degrading p53 to eliminating oncogenic targets such as BET proteins, while also blocking HDMX-mediated sequestration, thereby maximizing p53 reactivation in concert with cancer protein degradation. TAPTAC1 outperforms combination treatments and PROTACs that target HDM2 and BET proteins, but not HDMX, and is broadly effective in wild-type (WT) p53 cancers, including mouse models of osteosarcoma and leukemia. Importantly, TAPTAC1 leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity. With WT p53 retained in 90% of pediatric and 50% of adult cancers, TAPTACs provide a therapeutic platform for addressing key limitations of prior anti-cancer strategies.  \nINTRODUCTION  \nThe landmark discovery that a proteolysis targeting chimera (PROTAC) could be used to recruit an endogenous E3 ubiquitin ligase to degrade a pathologic target via the ubiquitin-proteasomal pathway (UPS) ushered in a new era of drug development based on eliminating rather than inhibiting disease-causing proteins.1 This mechanism circumvents traditional challenges ","cbCaimIPmQDgbQSy","https://ap.wps.com/l/cbCaimIPmQDgbQSy","pdf",9840362,25,"English","# Highlights\n## In brief\n# Summary\n# Introduction","[{\"question\":\"What is TAPTAC1 and how does it work in wild-type p53 cancers?\",\"answer\":\"TAPTAC1 is a triple-action PROTAC that reactivates apoptosis in wild-type p53 cancers. It inhibits HDM2 and HDMX to maximize p53 reactivation while using HDM2 to degrade oncogenic BET proteins.\"},{\"question\":\"Which targets does TAPTAC1 affect to achieve its therapeutic effect?\",\"answer\":\"TAPTAC1 targets HDM2 and HDMX to reprogram p53 signaling and also degrades oncogenic BET proteins. It achieves p53 reactivation alongside targeted protein degradation.\"},{\"question\":\"Why is TAPTAC1 described as broadly effective and potentially safer than some prior approaches?\",\"answer\":\"TAPTAC1 is broadly effective against wild-type p53 cancers, including mouse models, while sparing normal cells. It leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity.\"}]","A triple-action PROTAC for wild-type p53 cancer therapy | PDF",1790180226,63]