BSJ-5-63 is a potent, triple degrader targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, downregulates HRR genes and inhibits AR signaling.
BSJ-5-63 effectively induces CDK12 and CCNK degradation in PCa cell lines 22Rv1, LNCaP, and LNCaP-derived C4-2B in a dose- and time-dependent manner, whereas CDK13 protein levels remains unchanged.
BSJ-5-63 significantly attenuates the phosphorylation of RNA Pol II at Ser2, Ser5, and Ser7.
BSJ-5-63 effectively downregulates homologous recombination repair (HRR) genes, inhibits BRCA1 and BRCA2 mRNA expression and protein levels in 22Rv1, LNCaP, and DU145 cells, also reduces RAD51 protein levels, increases H2AX (H2AX phosphorylated at Ser 139).
BSJ-5-63 attenuates AR signaling through CDK7 and CDK9 degradation.
BSJ-5-63 induces a "BRCAness"state that persists for a significant duration, enabling sequential combination therapy with PARP inhibitors (PARPis) while potentially minimizing drug-related toxicity and resistance.
BSJ-5-63 (25 mg/kg) exhibited potent antiproliferative effects in both AR-positive and AR-negative CRPC models.