Discovery of a Potent Inhibitor of Replication Protein A Protein鈥揚rotein Interactions Using a Fragment-Linking Approach

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• 作者：Andreas O. Frank ; Michael D. Feldkamp ; J. Phillip Kennedy ; Alex G. Waterson ; Nicholas F. Pelz ; James D. Patrone ; Bhavatarini Vangamudi ; DeMarco V. Camper ; Olivia W. Rossanese ; Walter J. Chazin ; Stephen W. Fesik
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9242-9250
• 全文大小：494K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

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鈥損rotein 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鈥損rotein 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鈥搇igand 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鈥檚 interaction with ssDNA.