Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer.

ABSTRACT

Aberrant hyperactivation of cyclins results in carcinogenesis and therapy resistance in cancers. Direct degradation of the specific cyclin or cyclin-dependent kinase (CDK)-cyclin complex by small-molecule degraders remains a great challenge. Here, we applied the first application of hydrophobic tagging to induce degradation of CDK9-cyclin T1 heterodimer, which is required to keep productive transcription of oncogenes in cancers. LL-K9-3 was identified as a potent small-molecule degrader of CDK9-cyclin T1. Quantitative and time-resolved proteome profiling exhibited LL-K9-3 induced selective and synchronous degradation of CDK9 and cyclin T1. The expressions of androgen receptor (AR) and cMyc were reduced by LL-K9-3 in 22RV1 cells. LL-K9-3 exhibited enhanced anti-proliferative and pro-apoptotic effects compared with its parental CDK9 inhibitor SNS032 and suppressed downstream signaling of CDK9 and AR more effectively than SNS032. Moreover, LL-K9-3 inhibited AR and Myc-driven oncogenic transcriptional programs and exerted stronger inhibitory effects on several intrinsic target genes of AR than the monomeric CDK9 PROTAC (Thal-SNS032).