5D9L

Rsk2 N-terminal Kinase in Complex with bis-phenol pyrazole

Summary for 5D9L

• Entry DOI: 10.2210/pdb5d9l/pdb
• Related: 5D9K
• Descriptor: Ribosomal protein S6 kinase alpha-3, 4,4'-(1H-pyrazole-3,4-diyl)diphenol, GLYCEROL, ... (4 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51812
• Total number of polymer chains: 1
• Total formula weight: 37549.35

Authors

Appleton, B.A. (deposition date: 2015-08-18, release date: 2015-09-02, Last modification date: 2024-03-06)

Primary citation

Jain, R.,Mathur, M.,Lan, J.,Costales, A.,Atallah, G.,Ramurthy, S.,Subramanian, S.,Setti, L.,Feucht, P.,Warne, B.,Doyle, L.,Basham, S.,Jefferson, A.B.,Lindvall, M.,Appleton, B.A.,Shafer, C.M.
Discovery of Potent and Selective RSK Inhibitors as Biological Probes.
J.Med.Chem., 58:6766-6783, 2015

PubMed 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 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.

PubMed: 26270416
DOI: 10.1021/acs.jmedchem.5b00450

Experimental method

X-RAY DIFFRACTION (2.15 Å)