Abstract
Breast cancer gene 1 carboxy terminus (BRCT) domains are found in a number of proteins that are important for DNA damage response (DDR). The BRCT domains bind phosphorylated proteins, and these protein-protein interactions are essential for DDR and DNA repair. High affinity domain specific inhibitors are needed to facilitate the dissection of the protein-protein interactions in the DDR signaling. The BRCT domains of BRCA1 bind phosphorylated protein through a pSXXF consensus recognition motif. We identified a hydrophobic pocket at the P-1 position of the pSXXF binding site. Here we conducted a structure-guided synthesis of peptide analogues with hydrophobic functional groups at the P-1 position. Evaluation of these led to the identification of a peptide mimic 15 with a inhibitory constant (K i) of 40 nM for BRCT(BRCA1). Analysis of the TopBP1 and MDC1 BRCT domains suggests a similar approach is viable to design high affinity inhibitors.
Original language | English (US) |
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Pages (from-to) | 764-767 |
Number of pages | 4 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 2 |
Issue number | 10 |
DOIs | |
State | Published - Oct 13 2011 |
Keywords
- BRCT inhibitors and breast cancer
- Protein-protein interface
- peptide mimics
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry