[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-332414-105":59,"doc-detail-332414-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","expanded-profiling-of-wd-repeat-domain-5-inhibitors-reveals-actionable-strategies-for-the-treatment-of-hematologic-malignancies","Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies","","Expanded profiling evaluates small-molecule WD repeat domain 5 (WDR5) interaction-site inhibitors (WINi) across diverse cancer cell contexts, testing them alone and in combination with other agents. The findings show unexpected activity in both solid and blood-borne cancers, including tumors harboring mutant p53. In hematologic malignancies, WINi function as single agents for leukemia and diffuse large B cell lymphoma xenografts and combine with venetoclax to suppress disseminated acute myeloid leukemia in vivo.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/expanded-profiling-of-wd-repeat-domain-5-inhibitors-reveals-actionable-strategies-for-the-treatment-of-hematologic-malignancies/332414/",{"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/expanded-profiling-of-wd-repeat-domain-5-inhibitors-reveals-actionable-strategies-for-the-treatment-of-hematologic-malignancies/332414.png","ImageObject",300,407,{"name":92,"@type":93},"Asher","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-10","2026-09-21",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 does WDR5 do in cancer-related transcription regulation?","Question",{"text":112,"@type":113},"WDR5 is a nuclear protein that recruits MYC oncoprotein transcription factors to chromatin, stimulating ribosomal protein gene expression. It also serves as a scaffold for histone methyltransferase complexes involved in epigenetic regulation.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why is it difficult to predict which cancers will respond to WIN site inhibitors (WINi)?",{"text":117,"@type":113},"WINi disrupt only a specific subset of WDR5 activities, making them selective loss-of-function agents. Because of this selectivity and their unique mechanism, genome-wide knockout/knockdown resources may not directly predict sensitive cancer cell types.",{"name":119,"@type":110,"acceptedAnswer":120},"How effective are WINi in hematologic malignancy models, and what is the key combination partner?",{"text":121,"@type":113},"WINi show single-agent effectiveness in leukemia and diffuse large B cell lymphoma xenograft models. They can be combined with venetoclax to suppress disseminated acute myeloid leukemia in vivo.","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},332414,1790013072,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"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":52,"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},687197207639,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","RESEARCH ARTICLE  \nMEDICAL SCIENCES  \nExpanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies  \nChristian T. Meyera, b,1, Brianna N. Smithc,1, Jing Wangd,e, Kevin B. Teuscherf, Brian C. Griebg , Gregory C. Howardh , Alexander J. Silverg , Shelly L. Loreyh, Gordon M. Stotti , William J. Moorej , Taekyu Leef, Michael R. Savonag, April M. Weissmillerk , Qi Liud,e , Vito Quarantab,f,  \nStephen W. Fesikf, l, m , and William P. Tanseyf, h,2 Affiliations are included on p. 10.  \nEdited by Alexander Varshavsky, California Institute of Technology, Pasadena, CA; received May 3, 2024; accepted July 25, 2024  \nWD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine-binding cavity known as the “WIN” site. Multiple pharmacological inhibitors of the WDR5-interaction site of WDR5 (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice. Thus far, however, WINi have only been shown to be effective against a number of rare cancer types retaining wild-type p53. To explore the full potential of WINi for cancer therapy, we systematically profiled WINi across a panel of cancer cells, alone and in combination with other agents. We report that WINi are unexpectedly active against cells derived from both solid and blood-borne cancers, including those with mutant p53. Among hematologic malignancies, we find that WINi are effective as a single agent against leukemia and diffuse large B cell lymphoma xenograft models, and can be combined with the approved drug venetoclax to suppress disseminated acute myeloid leukemia in vivo. These studies reveal actionable strategies for the application of WINi to treat blood-borne cancers and forecast expanded utility ofWINi against other cancer types.  \nWDR5 | cancer therapy | ribosomes | venetoclax | lymphoma  \nWD Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that has gained prominence as a target for anticancer drug discovery (1) . Its best-known role is to scaffold the MLL/SET (mixed lineage leukemia/Su(var)3-9, E(z) and Trithorax) histone methyltransferase (HMT) complexes that methylate histone H3 lysine four, but WDR5 also scaffolds other epigenetic writer complexes and recruits MYC oncoproteins to chromatin to stimulate ribosomal protein gene (RPG) transcription (2) . Strategies to pharmacologically inhibit WDR5 are based on targeting one of two sites—the WDR5-binding motif site and the WDR5-interaction (WIN) site—that mediate interactions with partner proteins (2) . Most drug discovery campaigns target the WIN site (1), an arginine-binding cavity that tethers WDR5 to chromatin (3) and engages arginine-containing WIN motifs found in proteins such as the MLL/SET HMT enzymes (4) . Multiple small-molecule WIN site inhibitors (WINi) have been discovered (1), including those that are orally bioavailable, efficacious, and safe in rodents (5), forecasting that WINi will be ready for clinical vetting in the near future.  \nDespite progress in drug discovery, the cancer types in which WINi have documented efficacy are small and confined to rare cancers such as neuroblastoma (6), rhabdoid tumors (7), and MLL-rearranged (MLLr) acute myeloid leukemia (AML) (3, 8). Two factors make it difficult to know whether these cancer types represent the totality of those sensitive to WINi, or if there are other malignant settings in which these agents may be of benefit. First is the finding that WINi disrupt only a specific subset of WDR5 activities (9) and are thus selective loss of function agents. This selectivity may underlie their safety in vivo (5)—permitting a “common essential” protein such as WDR5 (10) to be inhibited without broad toxicity—but it also means that genome-wide resources (10), or individual studies of WDR5 knockout/kno","cbCaitJRXyomq5Ys","https://ap.wps.com/l/cbCaitJRXyomq5Ys","pdf",5955809,"English","# Background and rationale\n## WDR5 function and WIN site inhibition\n## Why broader efficacy was uncertain\n# Mechanism and experimental profiling\n## WINi effects on MYC-driven ribosomal protein transcription\n## Induction of p53-mediated apoptosis\n# Therapeutic findings\n## Single-agent activity in leukemia and DLBCL models\n## Combination with venetoclax in disseminated AML\n# Significance and implications","[{\"question\":\"What does WDR5 do in cancer-related transcription regulation?\",\"answer\":\"WDR5 is a nuclear protein that recruits MYC oncoprotein transcription factors to chromatin, stimulating ribosomal protein gene expression. It also serves as a scaffold for histone methyltransferase complexes involved in epigenetic regulation.\"},{\"question\":\"Why is it difficult to predict which cancers will respond to WIN site inhibitors (WINi)?\",\"answer\":\"WINi disrupt only a specific subset of WDR5 activities, making them selective loss-of-function agents. Because of this selectivity and their unique mechanism, genome-wide knockout/knockdown resources may not directly predict sensitive cancer cell types.\"},{\"question\":\"How effective are WINi in hematologic malignancy models, and what is the key combination partner?\",\"answer\":\"WINi show single-agent effectiveness in leukemia and diffuse large B cell lymphoma xenograft models. They can be combined with venetoclax to suppress disseminated acute myeloid leukemia in vivo.\"}]","Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies | PDF",1789998113,25]