{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Ghosh P"],"funding":["Congressionally Directed Medical Research Programs","Deutsche Krebshilfe","National Cancer Institute","NCI NIH HHS","Division of Cancer Prevention, National Cancer Institute"],"pubmed_abstract":["The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the <i>de novo</i> design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of"],"journal":["RSC chemical biology"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11494886"],"repository":["biostudies-literature"],"pubmed_title":["Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K."],"pmcid":["PMC11494886"],"funding_grant_id":["R01CA262530","R01 CA262530","P30-CA076292","70114008","W81XWH2210026","P30 CA076292"],"pubmed_authors":["Palve V","Anand K","Mosior J","Monastyrskyi A","Duckett D","Schmitz M","Schonbrunn E","Sun L","Zeleke ST","Roush WR","Grassie D","Frydman S","Ghosh P","Pandurangan T","Geyer M","Chan SC"],"additional_accession":[]},"is_claimable":false,"name":"Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.","description":"The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the <i>de novo</i> design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Oct","modification":"2026-07-15T10:57:58.594Z","creation":"2026-07-03T03:15:35.734Z"},"accession":"S-EPMC11494886","cross_references":{"pubmed":["39450271"],"doi":["10.1039/d4cb00190g"]}}