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Discovery of protein-protein interaction inhibitors of replication protein A

Patrone, JD and Kennedy, JP and Frank, AO and Feldkamp, MD and Vangamudi, B and Pelz, NF and Rossanese, OW and Waterson, AG and Chazin, WJ and Fesik, SW (2013) Discovery of protein-protein interaction inhibitors of replication protein A. ACS Medicinal Chemistry Letters. pp. 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 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 RPA inhibitors. 2013 American Chemical Society

Item Type: Article
Additional Information: pubid: 78 nvp_institute: NIBR contributor_address: (Patrone, Kennedy, Frank, Feldkamp, Vangamudi, Pelz, Rossanese, Chazin, Fesik) Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, United States (Waterson, Fesik) Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States (Waterson, Chazin, Fesik) Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States (Frank) Novartis Institutes for BioMedical Research (NIBR), Global Discovery Chemistry, Emeryville, CA 94608, United States
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21920

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