[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-379277-105":59,"doc-detail-379277-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","targeting-cullin-neddylation-for-cancer-and-fibrotic-diseases","Targeting cullin neddylation for cancer and fibrotic diseases","","Protein neddylation is a post-translational modification in which NEDD8 is conjugated to lysine residues of substrate proteins, and cullin family proteins are the best recognized targets within Cullin-RING ligases (CRLs). Since many neddylation pathway components become overactivated in cancers and fibrotic diseases, neddylation inhibition offers an emerging therapeutic strategy. MLN4924 has progressed into phase I/II/III trials for cancer treatment, and this work summarizes key enzymes, medicinal chemistry advances, and outlooks for targeting neddylation in both disease areas.",{"@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/targeting-cullin-neddylation-for-cancer-and-fibrotic-diseases/379277/",{"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/targeting-cullin-neddylation-for-cancer-and-fibrotic-diseases/379277.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is neddylation and why does it matter for cancer and fibrotic diseases?","Question",{"text":112,"@type":113},"Neddylation reversibly attaches the ubiquitin-like molecule NEDD8 to substrate proteins via an enzymatic cascade. Core pathway proteins are frequently overactivated in cancers and fibrotic diseases, making the pathway a therapeutic target.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which protein substrates are most strongly associated with neddylation?",{"text":117,"@type":113},"Cullin family proteins within Cullin-RING ligases (CRLs) are identified as the best recognized physiological substrates, and their neddylation activates CRLs.",{"name":119,"@type":110,"acceptedAnswer":120},"What role does the neddylation inhibitor MLN4924 play in treatment development?",{"text":121,"@type":113},"MLN4924 (Pevonedistat) is an NAE inhibitor that blocks neddylation of all cullins, inactivating CRLs and leading to accumulation of CRL-related cancer substrates. It has entered phase I/II/III clinical trials, and its preclinical effects include cell cycle arrest and apoptosis among other outcomes.","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},379277,1790867047,{"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":39,"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},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Review  \nIvyspring  \nInternational Publisher  \nTheranostics  \n2023; 13(14): 5017-5056. doi: 10.7150/thno.78876  \nTargeting cullin neddylation for cancer and fibrotic diseases  \nZhang-Xu He1,2\\#, Wei-guang Yang3\\#, Dan Zengyangzong2, Ge Gao2, Qian Zhang2, Hong-Min Liu2, Wen Zhao2􀀍 and Li-Ying Ma2,4,5􀀍  \n1. Pharmacy College, Henan University of Chinese Medicine, 450046, Zhengzhou, China.  \n2. State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.  \n3. Children's hospital affiliated of Zhengzhou university; Henan children's hospital; Zhengzhou children's hospital, Henan Zhengzhou 450000, China.  \n4. China Meheco Topfond Pharmaceutical Co., Zhumadian 463000, China.  \n5. Key Laboratory of Cardio-cerebrovascular Drug, Henan Province, Zhumadian 463000, China.  \n\\#: These authors contribute equally to this work.  \n*: These senior authors contribute equally to this work.  \n􀀍 Corresponding author: Zhao Wen, Ph.D, zhaowen100@139.com and Ma Li-Ying, Ph.D, [maliying@zzu.edu.cn](maliying@zzu.edu.cn).  \n© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [http://ivyspring.com/terms](http://ivyspring.com/terms) for full terms and conditions.  \nReceived: 2022.09.13; Accepted: 2023.04.12; Published: 2023.09.04  \nAbstract  \nProtein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.  \nKeywords: Cullin neddylation, Inhibitors, Cancer, Fibrotic diseases  \nIntroduction  \nNeddylation, a reversible post-translational modification, adds a ubiquitin-like molecule NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8) to a lysine residue of targeted substrate proteins through a three-step enzymatic cascade, catalyzed by NEDD8-activating enzyme E1 (NAE), NEDD8-conjugating enzyme E2s (UBC12/UBE2M or UBE2F) and substrate-specific NEDD8-E3 ligases (Figure 1) [1, 2] . Shortly, the mature NEDD8 is firstly adenylated and activated inan ATP-dependent manner by NAE, a heterodimer comprising NAE1/APPBP1 and UBA3/NAEβ . Next, the activated NEDD8 is transmitted to one of two E2s, UBE2F or UBC12 via a trans-thiolation reaction, and then conjugated to its substrate protein through  \ncovalent attachment by various substrate-specific NEDD8 E3 ligases, such as RBX1/2 or DCN1-5 [3, 4] . Besides, neddylated substrates could be deneddylated by deneddylases, such as COP9 signalosome and NEDD8 protease 1 [5-9] . The best-identified physiological substrates of neddylation are cullin family proteins of CRLs, including cullin-1, -2, -3, -4A,-4B, -5, -7 and-9. UBC12 mainly interacts with RBX1 to mediate the neddylation of cullin-1, -2, -3, -4A and-4B, while UBE2F is highly selective to theneddylation of RBX2-related cullin-5 [10-12] . Cullinneddylation results in activation of CRLs, which are the biggest family of E3 ubiquitin ligases and control the ubiquitination of up to 20% cellular protei","cbCairCuyNVALJ9E","https://ap.wps.com/l/cbCairCuyNVALJ9E","pdf",11243824,"English","# Abstract\n# Keywords\n# Introduction\n## Neddylation pathway and CRL activation\n## Physiological substrates: cullins and related E2/E3 enzymes\n## Disease relevance and prognosis\n## Targeted inhibition: MLN4924 and other neddylation inhibitors","[{\"question\":\"What is neddylation and why does it matter for cancer and fibrotic diseases?\",\"answer\":\"Neddylation reversibly attaches the ubiquitin-like molecule NEDD8 to substrate proteins via an enzymatic cascade. Core pathway proteins are frequently overactivated in cancers and fibrotic diseases, making the pathway a therapeutic target.\"},{\"question\":\"Which protein substrates are most strongly associated with neddylation?\",\"answer\":\"Cullin family proteins within Cullin-RING ligases (CRLs) are identified as the best recognized physiological substrates, and their neddylation activates CRLs.\"},{\"question\":\"What role does the neddylation inhibitor MLN4924 play in treatment development?\",\"answer\":\"MLN4924 (Pevonedistat) is an NAE inhibitor that blocks neddylation of all cullins, inactivating CRLs and leading to accumulation of CRL-related cancer substrates. It has entered phase I/II/III clinical trials, and its preclinical effects include cell cycle arrest and apoptosis among other outcomes.\"}]","Targeting cullin neddylation for cancer and fibrotic diseases | PDF",1790234860,101]