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Discovery of a potent inhibitor of replication protein A protein-protein interactions using a fragment-linking approach

Frank, AO and Feldkamp, MD and Kennedy, JP and Waterson, AG and Pelz, NF and Patrone, JD and Vangamudi, B and Camper, DV and Rossanese, OW and Chazin, WJ and Fesik, SW (2013) Discovery of a potent inhibitor of replication protein A protein-protein interactions using a fragment-linking approach. Journal of Medicinal Chemistry. pp. 9242-9250.

Abstract

Replication protein A (RPA), the major eukaryotic single-stranded DNA (ssDNA)-binding protein, is involved in nearly all cellular DNA transactions. The RPA N-terminal domain (RPA70N) is a recruitment site for proteins involved in DNA-damage response and repair. Selective inhibition of these protein-protein interactions has the potential to inhibit the DNA-damage response and to sensitize cancer cells to DNA-damaging agents without affecting other functions of RPA. To discover a potent, selective inhibitor of the RPA70N protein-protein interactions to test this hypothesis, we used NMR spectroscopy to identify fragment hits that bind to two adjacent sites in the basic cleft of RPA70N. High-resolution X-ray crystal structures of RPA70N-ligand complexes revealed how these fragments bind to RPA and guided the design of linked compounds that simultaneously occupy both sites. We have synthesized linked molecules that bind to RPA70N with submicromolar affinity and minimal disruption of RPA's interaction with ssDNA. 2013 American Chemical Society

Item Type: Article
Additional Information: pubid: 74 nvp_institute: NIBR contributor_address: (Frank, Feldkamp, Kennedy, Pelz, Patrone, Vangamudi, Camper, Rossanese, Chazin, Fesik) Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, United States (Frank, Feldkamp, Chazin, Fesik) Center for Structural Biology, Vanderbilt University, Nashville, TN 37232-8725, United States (Waterson, Fesik) Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6600, United States (Waterson, Chazin, Fesik) Department of Chemistry, Vanderbilt University, Nashville, TN 37232-1822, 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/21916

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