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Discovery of Cell-Permeable Inhibitors That Target the BRCT Domain of BRCA1 Protein by Using a Small-Molecule Microarray.
- Source :
-
Angewandte Chemie . Aug2014, Vol. 126 Issue 32, p8561-8566. 6p. - Publication Year :
- 2014
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00448249
- Volume :
- 126
- Issue :
- 32
- Database :
- Academic Search Index
- Journal :
- Angewandte Chemie
- Publication Type :
- Academic Journal
- Accession number :
- 97321240
- Full Text :
- https://doi.org/10.1002/ange.201405169