Skip to main content

Fesik Lab

Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.

AUTHORS

Patrone JDJames D , Kennedy JP J Phillip , Frank AO Andreas O , Feldkamp MD Michael D , Vangamudi B Bhavatarini , Pelz NF Nicholas F , Rossanese OW Olivia W , Waterson AG Alex G , Chazin WJ Walter J , Fesik SW Stephen W . ACS medicinal chemistry letters. 2013 7 11; 4(7). 601-605

ABSTRACT

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.