Novel quinazolin-4(3H)-one based Cyclin K degraders regulate alternative polyadenylation activity.

Phenotypic screening is gaining attention as a powerful method for identifying compounds that regulate cellular phenotypes of interest through novel mechanisms of action. Recently, a new modality of compounds, called molecular glues, which can induce the degradation of target proteins by forming ternary complexes of E3 ligases, has emerged from phenotypic screening. In this study, using global proteomic analysis, we identified a novel Cyclin K degrader, T4, which was previously discovered through phenotypic screening for alternative polyadenylation regulation. Our detailed mechanistic analysis revealed that T4 induced Cyclin K degradation, leading to the regulation of alternative polyadenylation. Additionally, we generated a more potent Cyclin K degrader, TR-213, through a structure-activity relationship study of T4. T4 and TR-213 are structurally distinct from other Cyclin K degraders and can be used as novel chemical tools to further analyze the degradation of Cyclin K and the regulation of alternative polyadenylation.