Discovery of LL-K8-22 : A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex.

The CDK8-cyclin C complex is an important anti-tumor target, but unlike CDK8, cyclin C remains undruggable. Modulators regulating cyclin C activity directly are still under development. Here, a series of hydrophobic tagging-based degraders of the CDK8-cyclin C complex were designed, synthesized, and evaluated to identify the first dual degrader, , which induced selective and synchronous degradation of CDK8 and cyclin C. Proteomic and immunoblot studies exhibited that significantly degraded CDK8 without reducing CDK19 and did not degrade other cyclin proteins except cyclin C. Moreover, showed enhanced anti-proliferative effects over its parental molecule, , with potency increased by 5-fold in MDA-MB-468 cells. exhibited more pronounced effects on CDK8-cyclin C downstream signaling than , suppressing STAT1 phosphorylation more persistently. RNA-sequencing analysis revealed that inhibited E2F- and MYC-driven carcinogenic transcriptional programs. Overall, is the first-in-class degrader of cyclin C and would be useful for studying the unknown functions of cyclin C.