Related Experiment Video

Updated: Jun 30, 2026

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
09:24

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

RAD51-targeting small molecule degrader sensitizes BRCA-proficient prostate cancer cells to PARP inhibitors via

Yanlin Jian1, Yibo Gao1, Tianyang Zhou1

  • 1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

Acta Pharmaceutica Sinica. B
|June 29, 2026
PubMed

Insights

A novel PROTAC molecule, G73, degrades RAD51 protein, restoring sensitivity to PARP inhibitors in resistant cancers. This approach broadens the application of PARP inhibitors beyond homologous recombination-deficient tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against homologous recombination (HR)-deficient tumors.
  • Resistance to PARP inhibitors arises from intact HR functionality or lack of HR-related mutations.
  • RAD51 is crucial for HR repair and a potential therapeutic target.

Purpose of the Study:

  • To develop a novel therapeutic strategy targeting RAD51 to overcome PARP inhibitor resistance.
  • To investigate the efficacy of a proteolysis-targeting chimera (PROTAC) in degrading RAD51.
  • To assess the synergistic effect of RAD51 degradation with PARP inhibition.

Main Methods:

  • Generation of a small-molecule PROTAC, G73, designed to degrade RAD51.
  • Evaluation of G73's concentration- and time-dependent degradation of RAD51.
  • Assessment of G73's impact on DNA double-strand break (DSB) repair.
  • Combination studies of G73 with the PARP inhibitor olaparib.

Main Results:

  • G73 effectively degrades RAD51, mimicking an HR-deficient phenotype.
  • Impaired DNA DSB repair was observed following G73 treatment.
  • G73 demonstrated synergistic effects with olaparib, inducing synthetic lethality.
  • Olaparib-resistant cancers were re-sensitized to PARP inhibition by G73.

Conclusions:

  • A small-molecule PROTAC strategy targeting RAD51 degradation can overcome resistance to PARP inhibitors.
  • This approach expands the therapeutic utility of PARP inhibitors to a broader patient population.
  • Degrading RAD51 offers a promising strategy for treating cancers resistant to current therapies.
Keywords:
BRCA2DegraderHomologous recombinationPARP inhibitorsProstate cancerRAD51ResistanceSynthetic lethality

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