Related Experiment Video

Updated: May 10, 2025

Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage
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Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage

Published on: January 31, 2018

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Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in

Fu Gui1, Baishan Jiang2, Jie Jiang2

  • 1Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Science Advances
|April 23, 2025
PubMed

Insights

A novel PROTAC, BSJ-5-63, degrades key CDKs to induce BRCAness and attenuate AR signaling. This dual-action approach shows potent antitumor activity in preclinical models of castration-resistant prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Advanced prostate cancer (PCa) treatments target the androgen receptor (AR) pathway.
  • Castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) are significant clinical challenges.

Purpose of the Study:

  • To introduce BSJ-5-63, a novel proteolysis-targeting chimera (PROTAC) designed to overcome resistance in advanced prostate cancer.
  • To evaluate the therapeutic potential of BSJ-5-63 by targeting multiple key pathways.

Main Methods:

  • BSJ-5-63, a PROTAC, was designed to degrade cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9.
  • Assessment of BSJ-5-63's effects on BRCA1/BRCA2 expression, DNA repair (BRCAness), AR signaling, and antitumor activity in vitro and in vivo CRPC models.

Main Results:

  • BSJ-5-63 degrades CDK12, leading to reduced BRCA1/BRCA2 expression and a "BRCAness" state, sensitizing cells to PARP inhibitors (PARPis).
  • Degradation of CDK7 and CDK9 by BSJ-5-63 attenuates AR signaling, enhancing therapeutic efficacy.
  • BSJ-5-63 demonstrated potent antitumor activity in both AR-positive and AR-negative CRPC models.

Conclusions:

  • BSJ-5-63 represents a promising therapeutic strategy for CRPC by simultaneously targeting DNA repair mechanisms and AR signaling.
  • This dual-action approach offers potential benefits for a broad patient population with advanced prostate cancer, addressing resistance to current therapies.

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