Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 7, Pages 36-40Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml400032y
Keywords
Replication protein A; DNA damage; fragment-based discovery
Categories
Funding
- NIH [5DP1OD006933/8DP1CA174419, R01GM065484]
- ARRA [5RC2CA148375]
- Deutscher Akademischer Austausch Dienst
- NIH NRSA
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Replication protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity toward DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Toward this end, we have discovered two lead series of compounds, derived from hits obtained from a fragment-based screen that bind to RPA70N with low micromolar affinity and inhibit the binding of an ATRIP-derived peptide to RPA. These compounds may offer a promising starting point for the discovery of clinically useful RP inhibitors.
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