[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-440739-105":59,"doc-detail-440739-en":130},{"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":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","a-breakthrough-in-nsclc-therapy-targeted-protein-degradation-of-cd26-via-protacs","A breakthrough in NSCLC therapy - targeted protein degradation of CD26 via PROTACs","","Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer cases, yet many patients lack actionable EGFR/ALK driver mutations and benefit only limitedly from chemotherapy. CD26 is overexpressed in most NSCLC cases but conventional inhibitors fail to disrupt its scaffolding and ADA interaction. A study in eBioMedicine reports the PROTAC degrader P4-3, which promotes CD26 degradation, triggers ADA translocation, adenosine depletion, ROS generation, DNA damage, and intrinsic apoptosis, with strong tumor inhibition in multiple models and minimal toxicity.",{"@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/a-breakthrough-in-nsclc-therapy-targeted-protein-degradation-of-cd26-via-protacs/440739/",{"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-breakthrough-in-nsclc-therapy-targeted-protein-degradation-of-cd26-via-protacs/440739.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-01","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is CD26 considered a promising target in NSCLC?","Question",{"text":112,"@type":113},"CD26 is a transmembrane glycoprotein overexpressed in more than 85% of NSCLC cases, making it useful as a diagnostic biomarker and therapeutic target.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What is distinctive about PROTAC targeting of CD26 compared with small-molecule inhibitors?",{"text":117,"@type":113},"Conventional inhibitors suppress CD26’s enzymatic activity only, whereas PROTACs catalytically degrade CD26 and can abolish both enzymatic and non-enzymatic scaffolding functions.",{"name":119,"@type":110,"acceptedAnswer":120},"How does P4-3 drive downstream anti-tumor effects?",{"text":121,"@type":113},"P4-3 induces CD26 degradation, leading to cytoplasmic translocation of membrane-bound ADA, adenosine depletion, mitochondrial ROS accumulation, DNA damage, and activation of the intrinsic apoptotic pathway.","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},440739,1791086792,{"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":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":14,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":24,"preview_page_count":4},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","Comment  \nA breakthrough in NSCLC therapy: targeted protein degradation of CD26 via PROTACs  \nXiaoling Guan, Xi-Yong Yu, and Lingmin Zhang∗  \nThe Affiliated Panyu Central Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China  \nNon-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases and remains a leading cause of cancer-related mortality worldwide.1 While current targeted therapies primarily address driver mutations such as those in EGFR and ALK,2 approximately 30%–40% of patients lack actionable mutations and thus derive limited benefit from existing regimens. Chemotherapy continues to serve as a mainstay treatment, yet its utility is constrained by modest efficacy, considerable toxicity, and frequent development of resistance. CD26 (dipeptidyl peptidase 4), a transmembrane glycoprotein overexpressed in more than 85% of NSCLC cases,3 represents a promising diagnostic biomarker and therapeutic target. Conventional small-molecule inhibitors only suppress its enzymatic activity, without disrupting its critical scaffolding function or interaction with membranebound adenosine deaminase (ADA), thereby yielding suboptimal clinical outcomes. Proteolysistargeting chimera (PROTAC) technology holds promise for overcoming drug resistance and enhancing selectivity through catalytic degradation of disease-relevant proteins.4 , 5 However, prior research has largely centered on kinase targets, leaving PROTAC-based strategies against CD26 in drivernegative NSCLC substantially underexplored. This gap underscores an urgent need for innovative therapeutic approaches.  \nIn a recent study published in eBioMedicine, Professor Gong et al.6 reported the design and synthesis of P4-3, a novel PROTAC degrader targeting CD26 . Moving beyond the traditional driver gene-centric paradigm, this work extended PROTAC technology to multifunctional membrane proteins such as CD26, offering anew therapeutic direction for driver-negative NSCLC. P4-3 promoted CD26 degradation via clathrindependent endocytosis and stabilized a CD26–P4- 3–CRBN ternary complex. It demonstrated excellent selectivity, showing no appreciable degradation of homologous enzymes within the DPP family.  \nDOI of original article: [https://doi.org/10.1016/j.ebiom.2025.106026](https://doi.org/10.1016/j.ebiom.2025.106026)  \n*Corresponding author.  \nE-mail address: [zhanglm@gzhmu.edu.cn](zhanglm@gzhmu.edu.cn) (L. Zhang).  \n© 2025 The Author(s) . Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ([http://creativecommons](http://creativecommons). org/licenses/by-nc-nd/4.0/) .  \nMechanistically, P4-3-induced CD26 degradation triggered cytoplasmic translocation of membrane-bound ADA, resulting in adenosine depletion, accumulation of mitochondrial reactive oxygen species (ROS), DNA damage, and subsequent activation of the intrinsic apoptotic pathway. In vitro, P4-3 potently inhibited proliferation and migration of driver-negative NSCLC cell lines (e.g., NCI-H460 and NCI-H1299), while exhibiting minimal toxicity toward normal bronchial epithelial cells. The compound also displayed robust anti-tumor activity across cell line-derived xenograft (CDX) models, orthotopic lung cancer models, and patient-derived organoids (PDOs), accompanied by a favorable safety profile devoid of significant hepatotoxicity, nephrotoxicity, or pancreatitis risk.  \nP4-3 operates through a distinctive metabolic regulatory mechanism independent of canonical pathways such as EGFR/AKT. It thus addresses a therapeutic void for patients lacking actionable targets and offers a potential alternative for those with acquired resistance to existing targeted therapies. A key advantage over conventional inhibitors lies in its capacity to concurrently abolish both the","cbCaieCjYt1d6IXI","https://ap.wps.com/l/cbCaieCjYt1d6IXI","pdf",111045,"English","# A breakthrough in NSCLC therapy\n## Targeting CD26 with PROTAC-mediated degradation\n## Mechanism and therapeutic effects of P4-3\n## Selectivity, efficacy, and safety across models\n## Limitations and future research directions","[{\"question\":\"Why is CD26 considered a promising target in NSCLC?\",\"answer\":\"CD26 is a transmembrane glycoprotein overexpressed in more than 85% of NSCLC cases, making it useful as a diagnostic biomarker and therapeutic target.\"},{\"question\":\"What is distinctive about PROTAC targeting of CD26 compared with small-molecule inhibitors?\",\"answer\":\"Conventional inhibitors suppress CD26’s enzymatic activity only, whereas PROTACs catalytically degrade CD26 and can abolish both enzymatic and non-enzymatic scaffolding functions.\"},{\"question\":\"How does P4-3 drive downstream anti-tumor effects?\",\"answer\":\"P4-3 induces CD26 degradation, leading to cytoplasmic translocation of membrane-bound ADA, adenosine depletion, mitochondrial ROS accumulation, DNA damage, and activation of the intrinsic apoptotic pathway.\"}]","A breakthrough in NSCLC therapy - targeted protein degradation of CD26 via PROTACs | PDF",1790693132]