Related Experiment Video
Updated: Apr 27, 2026
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Discovery of cell-permeable inhibitors that target the BRCT domain of BRCA1 protein by using a small-molecule
Zhenkun Na1, Sijun Pan, Mahesh Uttamchandani
1Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 (Singapore) http://staff.science.nus.edu.sg/∼syao.
Abstract:
BRCTs are phosphoserine-binding domains found in proteins involved in DNA repair, DNA damage response and cell cycle regulation. BRCA1 is a BRCT domain-containing, tumor-suppressing protein expressed in the cells of breast and other human tissues. Mutations in BRCA1 have been found in ca. 50% of hereditary breast cancers. Cell-permeable, small-molecule BRCA1 inhibitors are promising anticancer agents, but are not available currently. Herein, with the assist of microarray-based platforms, we have discovered the first cell-permeable protein-protein interaction (PPI) inhibitors against BRCA1. By targeting the (BRCT)2 domain, we showed compound 15 a and its prodrug 15 b inhibited BRCA1 activities in tumor cells, sensitized these cells to ionizing radiation-induced apoptosis, and showed synergistic inhibitory effect when used in combination with Olaparib (a small-molecule inhibitor of poly-ADP-ribose polymerase) and Etoposide (a small-molecule inhibitor of topoisomerase II). Unlike previously reported peptide-based PPI inhibitors of BRCA1, our compounds are small-molecule-like and could be directly administered to tumor cells, thus making them useful for future studies of BRCA1/PARP-related pathways in DNA damage and repair response, and in cancer therapy.
Insights
Researchers developed novel small-molecule inhibitors targeting BRCA1 (Breast Cancer gene 1) protein interactions. These compounds show potential for cancer therapy by sensitizing tumor cells to DNA damage treatments and enhancing drug efficacy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- BRCT domains are crucial for DNA repair and cell cycle regulation.
- BRCA1, a tumor suppressor with BRCT domains, is implicated in hereditary breast cancers.
- Targeting BRCA1 with small molecules offers a promising anticancer strategy, but effective inhibitors are lacking.
Purpose of the Study:
- To discover and characterize the first cell-permeable, small-molecule inhibitors of BRCA1 protein-protein interactions (PPIs).
- To evaluate the efficacy of these inhibitors in cancer cells and their potential in combination therapies.
Main Methods:
- Utilized microarray-based platforms to identify BRCA1 PPI inhibitors.
- Synthesized and tested compound 15a and its prodrug 15b targeting the BRCA1 (BRCT)2 domain.
- Assessed compound effects on BRCA1 activity, apoptosis induction, and synergistic effects with other anticancer agents.
Main Results:
- Compound 15a and prodrug 15b demonstrated cell permeability and inhibited BRCA1 activity in tumor cells.
- These compounds sensitized cells to ionizing radiation-induced apoptosis.
- A synergistic inhibitory effect was observed when combined with Olaparib and Etoposide.
Conclusions:
- The developed small-molecule inhibitors represent a novel class of cell-permeable BRCA1 inhibitors.
- These compounds hold promise for cancer therapy, particularly in BRCA1/PARP-related DNA damage and repair pathways.
- Their small-molecule nature allows direct administration, facilitating further research and therapeutic applications.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34DNA Microarrays