[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-378717-105":59,"doc-detail-378717-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","addressing-transcriptional-dysregulation-in-cancer-through-cdk9-inhibition-article","Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition - Article","","Undermining transcriptional addiction and dependence on selected transcriptional programs is essential for tackling cancers with major unmet clinical need. Cyclin-dependent kinase 9 (CDK9) is a therapeutically actionable regulator of transcription because it coordinates events controlling RNA polymerase II pause-release. Yet clinical targeting has been difficult due to severe cytotoxicity from CDK9’s essentiality and early pan-CDK inhibitor polypharmacology. Selective molecules in early clinical evaluation renew therapeutic hope.",{"@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/addressing-transcriptional-dysregulation-in-cancer-through-cdk9-inhibition-article/378717/",{"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/addressing-transcriptional-dysregulation-in-cancer-through-cdk9-inhibition-article/378717.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","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 transcriptional dysregulation important in cancer treatment?","Question",{"text":112,"@type":113},"Transcriptional programs are often dysregulated in cancer and linked to genetic alterations relevant to molecular pathogenesis. Addressing these networks can benefit patients with cancers driven by transcriptional dependencies.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What role does CDK9 play in transcription regulation?",{"text":117,"@type":113},"CDK9 coordinates biochemical events that regulate RNA polymerase II pause-release. It phosphorylates components related to the paused complex and supports formation of the elongation complex, enabling productive transcription.",{"name":119,"@type":110,"acceptedAnswer":120},"What has historically limited CDK9 targeting in the clinic?",{"text":121,"@type":113},"Clinical targeting has been elusive due to often intolerable cytotoxicity arising from CDK9 essentiality across many cell lineages and due to polypharmacology of early pan-CDK inhibitors.","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},378717,1790846723,{"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":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},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","[pubs.acs.org/biochemistry](pubs.acs.org/biochemistry)  From the Bench   \nAddressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition  \nMohammed A. Toure and Angela N. Koehler *  \n Cite This: Biochemistry 2023, 62, 1114−1123  \nRead Online  \n\n|  |  |  |  |\n| --- | --- | --- | --- |\n| ACCESS   | Metrics & More |  |  Article Recommendations |\n\nABSTRACT: Undermining transcriptional addiction, the dependence of cancerson selected transcriptional programs, is critically important for addressing cancers with high unmet clinical need. Cyclin-dependent kinase 9 (CDK9) has long been considered an actionable therapeutic target for modulating transcription in many diseases. This appeal is due to its role in coordinating the biochemical events that regulate RNA polymerase II (RNA Pol II) pause-release state, one that offers a way for attenuating transcriptional dysregulation driven by amplified or overexpressed transcription factors implicated in cancer. However, targeting CDK9 in the clinic has historically proven elusive, a challenge that stems from the often highly intolerable cytotoxicity attributed to its essentiality across many cell lineages and the polypharmacology of the first generation of pan-CDK inhibitors to reach the clinic. A new wave of highly selective molecules progressing through the early stages of clinical evaluation offers renewed hope.  \n■ INTRODUCTION  \nGenomic profiling to determine the molecular drivers of  \ndisease (e.g., mutations or gene expression becoming an important pillar of modern genomic  \npatterns) is medicine. 1−3  \nThis is particularly true in the context of cancer, wherein dysregulation of transcriptional programs is often associated with genetic alterations with established relevance to molecular pathogenesis.1,2,4,5 In fact, an entire area of precision cancer medicine is dedicated to the discovery and modulation of the molecular regulatory nodes in transcriptional networks that could offer therapeutic benefits to cancer patients.1,6−8  \nDNA-binding transcription factors are chiefly responsible for the regulation of gene expression.9 They are commonly dysregulated in cancer, and some cancers are heavily reliant or addicted to select transcription factors such as MYC.5 Direct inhibition of these transcription factors has long been the focus of many drug development and design efforts against cancer.4 However, this task remains largely elusive due to their lack of established ligandable pockets and large protein−protein interaction interfaces.1,4 One strategy for addressing these inherent challenges is to target druggable proteins that regulate the activation or stability of transcription factors driving a particular disease.10, 11  \nTranscription-associated cyclin-dependent kinases or tCDKs  \n(e.g., CDK7, the signaling  \nCDK8, CDK9, CDK12, CDK13) govern most of events that regulate productive transcription.10, 12  \nBroadly, they are primarily known for their phosphorylation of residues at the carboxy-terminal domain of RNA Pol II to drive the initiation, elongation, and termination of transcription.10, 13 Moreover, they are often involved in regulating the activation,  \nrecruitment, and stability of the transcription factors with which they interact.10, 13, 14 Unlike DNA-binding transcription factors, tCDKs are structurally amenable to pharmacological perturbation. Although drug candidates primarily targeting tCDKs are yet to receive FDA approval, the general kinase target class boasts a large share of approved therapies.15, 16 Roskoski (ref 15) and Cohen et al. (ref 16) provide detailed reviews of drug discovery against kinases.  \nThe cyclin-dependent kinase 9 (CDK9) is a transcriptional kinase that has attracted recent interest as a clinically relevant target. Given its role as a global regulator of transcription and a critical node in multiple oncogenic transcriptional networks, CDK9 is viewed as an actionable target in a variety of transcriptionally addicted cancers,5 including man","cbCailOpvvs1NNOc","https://ap.wps.com/l/cbCailOpvvs1NNOc","pdf",4546685,"English","# INTRODUCTION\n## Genomic profiling and dysregulated transcriptional programs\n## Targeting transcription factors and limitations\n## Drugging transcription-associated cyclin-dependent kinases (tCDKs)\n## CDK9 as a clinically relevant transcriptional kinase\n## Overview of inhibitor discovery and clinical evaluation","[{\"question\":\"Why is transcriptional dysregulation important in cancer treatment?\",\"answer\":\"Transcriptional programs are often dysregulated in cancer and linked to genetic alterations relevant to molecular pathogenesis. Addressing these networks can benefit patients with cancers driven by transcriptional dependencies.\"},{\"question\":\"What role does CDK9 play in transcription regulation?\",\"answer\":\"CDK9 coordinates biochemical events that regulate RNA polymerase II pause-release. It phosphorylates components related to the paused complex and supports formation of the elongation complex, enabling productive transcription.\"},{\"question\":\"What has historically limited CDK9 targeting in the clinic?\",\"answer\":\"Clinical targeting has been elusive due to often intolerable cytotoxicity arising from CDK9 essentiality across many cell lineages and due to polypharmacology of early pan-CDK inhibitors.\"}]","Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition - Article | PDF",1790232068,25]