He/Him/His
Job Title
Research Scientist
Academic Rank
Research Scientist
Department
Urology
Authors
Fu Gui*, PhD, Baishan Jiang, PhD, Jie Jiang, PhD, Zhixiang He, MSc, Takuya Tsujino, MD, PhD, Tomoaki Takai, MD, PhD, Seiji Arai, MD, PhD, Celine Pana, PhD, Jens Köllermann, MD, Gary Andrew Bradshaw, PhD, Robyn Eisert, PhD, Marian Kalocsay, PhD, Anne Fassl, PhD, Steven P Balk, MD, PhD, Adam S. Kibel, MD, Li Jia, PhD
Categories
Tags
Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) signaling pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR signaling inhibitors (ARSIs) remains a significant clinical challenge. Here, we present BSJ-5-63, a novel proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multi-pronged approach to CRPC therapy. BSJ-5-63 effectively degrades CDK12, resulting in diminished BRCA1 and BRCA2 expression and induction of a sustained “BRCAness” state. This sensitizes cancer cells to PARP inhibitors (PARPis), thereby extending therapeutic benefits to patients regardless of their homologous recombination repair (HRR) status. Furthermore, the degradation of CDK7 and CDK9 by BSJ-5-63 significantly 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 anti-tumor activity in both AR-positive and AR-negative setting. This study introduces BSJ-5-63 as a promising therapeutic agent that disrupts key pathways in CRPC, addressing both DNA repair and AR signaling mechanisms, with potential implications for a board patient population.
