Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A

作者：Patrone James D; Kennedy J Phillip; Frank Andreas O; Feldkamp Michael D; Vangamudi Bhavatarini; Pelz Nicholas F; Rossanese Olivia W; Waterson Alex G; Chazin Walter J; Fesik Stephen W^*

来源：ACS Medicinal Chemistry Letters, 2013, 4(7): 36-40.

DOI：10.1021/ml400032y

• Replication protein A
• DNA damage
• fragment-based discovery

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.

• 出版日期2013-7