[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-466264-105":59,"doc-detail-466264-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","an-update-on-clinically-advanced-protac-degraders-and-their-synthesis","An Update on Clinically Advanced PROTAC Degraders and Their Synthesis","","Proteolysis-targeting chimeras (PROTACs) enable targeted degradation of therapeutically relevant proteins via the ubiquitin-proteasome system (UPS), offering a differentiated alternative to traditional small-molecule inhibitors. By using bifunctional molecules, PROTACs can achieve increased specificity, catalytic behavior, and the potential to tackle targets considered previously undruggable. Since their conception roughly 20 years ago, PROTACs have advanced rapidly toward first clinical approval. This review surveys PROTAC targets, clinical development milestones, and the design and detailed synthesis of degrader molecules reaching clinical trials.",{"@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/an-update-on-clinically-advanced-protac-degraders-and-their-synthesis/466264/",{"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/an-update-on-clinically-advanced-protac-degraders-and-their-synthesis/466264.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-30",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},"What makes PROTACs different from traditional small-molecule inhibitors?","Question",{"text":112,"@type":113},"PROTACs use bifunctional molecules to induce targeted protein degradation through the UPS, rather than inhibiting a protein’s activity directly.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What therapeutic advances does the review highlight for PROTACs reaching clinical use?",{"text":117,"@type":113},"It summarizes PROTAC targets, progress in clinical development, and the design and detailed synthesis of degrader molecules that have advanced into clinical trials.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is androgen receptor (AR) a key target discussed in PROTAC development?",{"text":121,"@type":113},"The review explains that AR drives prostate cancer biology and that AR mutations often cause resistance to current therapies, creating a need for strategies that can eliminate the receptor.","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},466264,1790842059,{"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":36,"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":144,"preview_page_count":4},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Review  \nAn Update on Clinically Advanced PROTAC Degraders and Their Synthesis  \nRanjan Kumar Acharyya 1,†, Yugandhar Kothapalli 2,†, Suresh Yarlagadda 3, Chayan K. De 4, Srinivasa Rao Allu 1, Joyeeta Roy 5 and Rohan Kalyan Rej 1, *  \nAcademic Editor: Gheorghita Zbancioc  \nReceived: 15 November 2025  \nRevised: 15 December 2025  \nAccepted: 17 December 2025  \nPublished: 22 December 2025  \nCopyright: © 2025 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.  \n1 Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA  \n2 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA  \n3 Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA  \n4 Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA  \n5 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA  \n* Correspondence: [rohanrej@umich.edu](rohanrej@umich.edu)[ ](rohanrej@umich.edu)† These authors contributed equally to this work.  \nAbstract  \nProteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary therapeutic modality that enables degradation of therapeutically relevant proteins through the protein disposal machinery, the ubiquitin-proteasome system (UPS) . Unlike traditional smallmolecule inhibitors, PROTACs harness bifunctional molecules to induce targeted protein degradation, offering advantages such as increased specificity, catalytic activity, and the potential to address previously undruggable targets. Since their conception 20 years ago, PROTACs have made significant strides in target protein degradation (TPD), and today, PROTACs are on the verge of their first clinical approval. This review presents a detailed overview of PROTAC targets, clinical development progress, and the design and detailed synthesis of degrader molecules that have advanced to clinical trials.  \nKeywords: proteolysis-targeting chimeras (PROTACs); target protein degradation (TPD); cancer; anti-cancer agents  \n1. Introduction  \nTargeted protein degradation has emerged as a transformative concept in modern drug discovery, offering novel strategies for intervention in cellular processes previously deemed “undruggable.” In 2001, Sakamoto et al. revolutionized the field of protein degradation with the first demonstration of the concept of PROTAC technology [1–3] . Over the next decade, this innovative approach captured the attention of biotech companies and academic institutions. Among the pioneering advancements were Bavdegalutamide (ARV-110) and Vepdegestrant (ARV-471), which were among the first compounds to enter clinical trials [4,5] . On 8 August 2025 FDA has accepted a New Drug Application (NDA) for Vepdegestrant for the treatment of ESR1-mutated ER+/HER2-advanced breast cancer patients based on the pivotal Phase 3 VERITAC-2 clinical trial (NCT05654623), demonstrating statistically significant and clinically meaningful improvement in median progression-free survival (PFS) compared to Fulvestrant [6,7] .  \nRecent research indicates a significant rise in the utilization of different E3 ligases in PROTAC development, highlighting the expanding scope of targeted protein degradation strategies [8–10] . Among these, E3 ligases Von Hippel–Lindau (VHL) and Cereblon  \n(CRBN)-based PROTAC degraders have progressed to clinical development [11–14] . PROTAC technology has now been successfully used to target more than 100 proteins. This review offers a comprehensive overview of disclosed PROTAC degrader cancer targets, clinical development progress, and the design and detailed synthesis of degrader molecules (Figure 1) [13,15] .  \nFigure 1. Disclosed structures of PROTACs in the clinical trial.  \n2. Discussion of Targets, Clinical Development Progress, ","cbCaidJSsS6qiopt","https://ap.wps.com/l/cbCaidJSsS6qiopt","pdf",2457606,"English","# Introduction\n# Discussion of Targets, Clinical Development Progress, and the Design and Detailed Synthesis of Degrader Molecules\n## PROTACS Targeting Androgen Receptor (AR)","[{\"question\":\"What makes PROTACs different from traditional small-molecule inhibitors?\",\"answer\":\"PROTACs use bifunctional molecules to induce targeted protein degradation through the UPS, rather than inhibiting a protein’s activity directly.\"},{\"question\":\"What therapeutic advances does the review highlight for PROTACs reaching clinical use?\",\"answer\":\"It summarizes PROTAC targets, progress in clinical development, and the design and detailed synthesis of degrader molecules that have advanced into clinical trials.\"},{\"question\":\"Why is androgen receptor (AR) a key target discussed in PROTAC development?\",\"answer\":\"The review explains that AR drives prostate cancer biology and that AR mutations often cause resistance to current therapies, creating a need for strategies that can eliminate the receptor.\"}]","An Update on Clinically Advanced PROTAC Degraders and Their Synthesis | PDF",1790770923,101]