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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 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 expression of androgen receptor (AR) and c-Myc were reduced by LL-K9-3 in 22RV1 cells. LL-K9-3 exhibited enhanced anti-proliferative and pro-apoptotic effects than 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).

ORGANISM(S): Homo sapiens

PROVIDER: GSE205363 | GEO | 2022/06/05

REPOSITORIES: GEO

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