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Development of Potent RSK Inhibitors as Biological Probes

Jain, Rama and Mathur, Michelle and Jiong, Lan and Abran, Costales and Gordana, Atallah and Ramurthy, Savithri and Subramanian, Sharadha and Lina, Setti and Feucht, Paul and Warne, Robert and Laura, Doyle and Steven, Basham and Anne, Jefferson and Lindvall, Mika and Brent, Appleton and Shafer, Cynthia (2015) Development of Potent RSK Inhibitors as Biological Probes. Journal of Medicinal Chemistry, 58 (17). pp. 6766-6783. ISSN 0022-26231520-4804

Abstract

While the p90 Ribosomal S6 Kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective tool inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridines inhibitors of the RSK kinase family as demonstrated cellularly by inhibition of YB1 phosphorylation. These compounds provide for the first time in vitro tools with an improved selectivity and potency profile to examine the importance of RSK signaling in cancer cells and to fully evaluate RSK as a therapeutic target.

Item Type: Article
Date Deposited: 02 May 2016 23:45
Last Modified: 02 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/24442

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