Discovery of HyT‐Based Degraders of CDK9‐Cyclin T1 Complex

Abstract Direct modulation of the non‐kinase functions of cyclin and CDK‐cyclin complexes poses challenges. We utilize hydrophobic tag (HyT) based small‐molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. LL‐CDK9‐12 demonstrated the most potent and selective degradation ability, with DC 50 values of 0.362 μM against CDK9 and 0.680 μM against cyclin T1. In prostate cancer cells, LL‐CDK9‐12 showed enhanced anti‐proliferative activity than its parental molecule SNS032 and LL‐K9‐3, the previous reported CDK9‐cyclin T1 degrader. Moreover, LL‐CDK9‐12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL‐CDK9‐12 was an effective dual degrader of CDK9‐cyclin T1 and helped study the unknown function of CDK9‐cyclin T1. These results suggest that HyT‐based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes′ degraders.