LL-K8-22 is a potent, selective and durable PROTAC CDK8-cyclin C dual degrader, with DC 50 values of 2.52 and 2.64 μM, respectively. LL-K8-22 also suppresses STAT1 Ser 727 phosphorylation. LL-K8-22 inhibits E2F- and MYC-driven carcinogenic transcriptional programs. LL-K8-22 can be used for triplenegative breast cancer (TNBC) research. (Pink: Ligand for target protein ; Black: Linker ; Blue: Ligand for E3 ligase ).