Discovery of Potent and Selective RSK Inhibitors as Biological Probes.


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 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 pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the 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.

DOI: 10.1021/acs.jmedchem.5b00450

Cite this paper

@article{Jain2015DiscoveryOP, title={Discovery of Potent and Selective RSK Inhibitors as Biological Probes.}, author={Rama Jain and Michelle Mathur and Jiong Lan and Abran Costales and Gordana Atallah and Savithri Ramurthy and Sharadha Subramanian and Lina Q Setti and Paul H Feucht and Bob Warne and Laura V. Doyle and Stephen E Basham and Anne Bennett Jefferson and Mika K. Lindvall and Brent A. Appleton and Cynthia M Shafer}, journal={Journal of medicinal chemistry}, year={2015}, volume={58 17}, pages={6766-83} }