Open AccessDiscovery of Protein–Protein Interaction Inhibitors of Replication Protein A
Author(s) -
James D. Patrone,
J. Phillip Kennedy,
Andreas O. Frank,
Michael D. Feldkamp,
Bhavatarini Vangamudi,
Nicholas F. Pelz,
Olivia W. Rossanese,
Alex G. Waterson,
Walter Chazin,
Stephen W. Fesik
Publication year - 2013
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml400032y
Subject(s) - replication protein a , dna replication , drug discovery , replication factor c , protein subunit , chemistry , protein–protein interaction , computational biology , dna damage , ter protein , seqa protein domain , dna , microbiology and biotechnology , eukaryotic dna replication , biochemistry , biology , dna binding protein , gene , transcription factor
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 towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards 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 RPA inhibitors.
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