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Murine Double Minute 2 (MDM2) is a central negative regulator of p53, and reactivating p53 by blocking the MDM2–p53 interaction offers a therapeutic strategy. XR-4, a synthesized dimer spiroindolinone pyrrolidinecarboxamide, shows potent MDM2-p53 inhibitory activity with reduced off-target risks. XR-4 suppresses proliferation and induces apoptosis in cancer cells through p53 accumulation, p21 and PUMA upregulation, and MDM2 degradation via homo-PROTAC behavior, supported by in vitro and xenograft studies with favourable safety.",{"@graph":69,"@context":122},[70,84,105],{"@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/synthesis-and-antineoplastic-activity-of-a-dimer-spiroindolinone-pyrrolidinecarboxamide/381121/",{"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/synthesis-and-antineoplastic-activity-of-a-dimer-spiroindolinone-pyrrolidinecarboxamide/381121.png","ImageObject",300,407,{"name":92,"@type":93},"Theodore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-02","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is p53 reactivation considered important in cancer therapy?","Question",{"text":112,"@type":113},"p53 loss or mutation disrupts tumour suppression, promoting abnormal proliferation and tumorigenesis. Reactivating p53 can counter these processes and restore downstream anti-tumour responses.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What is the role of MDM2 in the p53 pathway?",{"text":117,"@type":113},"MDM2 negatively regulates wild-type p53 at multiple levels, including controlling protein stability and limiting p53 transcriptional activity, forming an autoregulatory loop with p53.",{"name":119,"@type":110,"acceptedAnswer":120},"How does XR-4 exert antineoplastic effects in the study?",{"text":121,"@type":113},"XR-4 inhibits the MDM2–p53 axis, induces wild-type p53 accumulation, upregulates p53 target genes p21 and PUMA, blocks proliferation, and triggers apoptosis, with evidence for MDM2 degradation via homo-PROTAC activity and strong in vivo efficacy.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},381121,1790342320,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},7971461740886,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","molecules   \nArticle  \nSynthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide  \nJingyi Cui 1,2, Yujie Wang 3, Xiaoxin Li 3, Fei Xiao 1,2,*, Hongjun Ren 4,* and Meng Wu 3, *  \nCitation: Cui, J.; Wang, Y.; Li, X.; Xiao, F.; Ren, H.; Wu, M. Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide. Molecules 2023, 28, 3912. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/molecules28093912](10.3390/molecules28093912)  \nAcademic Editors: Mei-Chin Lu, Mohamed El-Shazly and Kyoko Nakagawa-Goto  \nReceived: 23 March 2023  \nRevised: 27 April 2023  \nAccepted: 3 May 2023  \nPublished: 5 May 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 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, China  \n2 Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences,  \n9 DongDan Santiao, Beijing 100730, China  \n3 Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China  \n4 Advanced Research Institute and Department of Chemistry, Taizhou University, Taizhou 318000, China  \n* Correspondence: [xiaofei3965@bjhmoh.cn](xiaofei3965@bjhmoh.cn) (F.X.); [renhj@tzc.edu.cn](renhj@tzc.edu.cn) (H.R.); [wumeng@pumch.cn](wumeng@pumch.cn) (M.W.)  \nAbstract: The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53 . p53 reactivation by inhibiting MDM2–p53 interaction represents a promising therapeutic option in cancer treatment. Here, to develop more effective MDM2 inhibitors with lower off-target toxicities, we synthesized a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, with potent MDM2-p53 inhibition activity. Western blotting and qRT-PCR were performed to detect the impact of XR-4 on MDM2 and p53 protein levels and p53 downstream target gene levels in different cancers. Cancer cell proliferation inhibition and clonogenic activity were also investigated via the CCK8 assay and colony formation assay. A subcutaneous 22Rv1-derived xenografts mice model was used to investigate the in vivo anti-tumour activity of XR-4 . The results reveal that XR-4 can induce wild-type p53 accumulation in cancer cells, upregulate the levels of the p53 target genes p21 and PUMA levels, and then inhibit cancer cell proliferation and induce cell apoptosis. XR-4 can also act as a homo-PROTAC that induces MDM2 protein degradation. Meanwhile, the in vivo study results show that XR-4 possesses potent antitumour efficacy and a favourable safety property. In summary, XR-4 is an interesting spiroindolinone pyrrolidinecarboxamide-derivative dimer with effective p53 activation activity and a cancer inhibition ability.  \nKeywords: MDM2 inhibitor; p53 activation; dimer spiroindolinone pyrrolidinecarboxamide; cancer treatment  \n1. Introduction  \nAs of 2020, there were 19.3 million new cancer cases and there had been nearly 10 million cancer deaths in the world, making it one of the leading causes of death for humans all over the world [1] . Changes in many oncogenes and tumour suppressor genes are associated with human cancers, these genetic changes appear at different stages from canceration to cancer cell growth, proliferation, and metastasis [2,3] . The apoptosis of normal somatic ","cbCaik4cMr16EFzm","https://ap.wps.com/l/cbCaik4cMr16EFzm","pdf",3957535,13,"English","# 1. Introduction\n## 2. Abstract (Summary)\n## 3. Keywords and Research Focus","[{\"question\":\"Why is p53 reactivation considered important in cancer therapy?\",\"answer\":\"p53 loss or mutation disrupts tumour suppression, promoting abnormal proliferation and tumorigenesis. Reactivating p53 can counter these processes and restore downstream anti-tumour responses.\"},{\"question\":\"What is the role of MDM2 in the p53 pathway?\",\"answer\":\"MDM2 negatively regulates wild-type p53 at multiple levels, including controlling protein stability and limiting p53 transcriptional activity, forming an autoregulatory loop with p53.\"},{\"question\":\"How does XR-4 exert antineoplastic effects in the study?\",\"answer\":\"XR-4 inhibits the MDM2–p53 axis, induces wild-type p53 accumulation, upregulates p53 target genes p21 and PUMA, blocks proliferation, and triggers apoptosis, with evidence for MDM2 degradation via homo-PROTAC activity and strong in vivo efficacy.\"}]","Synthesis and Antineoplastic Activity of a Dimer - Spiroindolinone Pyrrolidinecarboxamide | PDF",1790243694,33]