Faculty, Staff and Student Publications
Publication Date
4-25-2025
Journal
Science Advances
Abstract
Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including both in vitro and in vivo CRPC models, demonstrate that BSJ-5-63 exerts potent antitumor activity in both AR-positive and AR-negative setting. This study introduces BSJ-5-63 as a promising therapeutic agent that addresses both DNA repair and AR signaling mechanisms, with potential benefits for a board patient population.
Keywords
Male, Humans, Poly(ADP-ribose) Polymerase Inhibitors, Receptors, Androgen, Cyclin-Dependent Kinases, Cell Line, Tumor, Signal Transduction, Animals, Proteolysis, BRCA1 Protein, BRCA2 Protein, Mice, Cyclin-Dependent Kinase-Activating Kinase, Xenograft Model Antitumor Assays, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Cyclin-Dependent Kinase 9
DOI
10.1126/sciadv.adu0847
PMID
40267193
PMCID
PMC12017310
PubMedCentral® Posted Date
4-23-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons