biostudies-literatureUnknownGhosh PCongressionally Directed Medical Research ProgramsDeutsche KrebshilfeNational Cancer InstituteNCI NIH HHSDivision of Cancer Prevention, National Cancer InstituteThe 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 ofRSC chemical biologyhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC11494886biostudies-literatureDiscovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.PMC11494886R01CA262530R01 CA262530P30-CA07629270114008W81XWH2210026P30 CA076292Palve VAnand KMosior JMonastyrskyi ADuckett DSchmitz MSchonbrunn ESun LZeleke STRoush WRGrassie DFrydman SGhosh PPandurangan TGeyer MChan SCfalseDiscovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.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 of2024-01-01T00:00:00Z2024 Oct2026-07-15T10:57:58.594Z2026-07-03T03:15:35.734ZS-EPMC114948863945027110.1039/d4cb00190g