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...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-09, Vol.58 (17), p.6766-6783 |
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| container_title | Journal of medicinal chemistry |
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| creator | Jain, Rama Mathur, Michelle Lan, Jiong Costales, Abran Atallah, Gordana Ramurthy, Savithri Subramanian, Sharadha Setti, Lina Feucht, Paul Warne, Bob Doyle, Laura Basham, Stephen Jefferson, Anne B. Lindvall, Mika Appleton, Brent A. Shafer, Cynthia M. |
| description | 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_str_mv | 10.1021/acs.jmedchem.5b00450 |
| format | Article |
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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. 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Med. Chem</addtitle><description>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.</description><subject>Animals</subject><subject>Cell Line</subject><subject>Crystallography, X-Ray</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Phosphorylation</subject><subject>Protein Conformation</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats, Sprague-Dawley</subject><subject>Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors</subject><subject>Signal Transduction</subject><subject>Structure-Activity Relationship</subject><subject>Y-Box-Binding Protein 1 - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMlOwzAQhi0EomV5A4R85JIy3rIcoRSoqERF4RzZjkNTJXGxk0p9ewxtOXIazcz_z_IhdEVgRICSW6n9aNWYQi9NMxIKgAs4QkMiKEQ8BX6MhgCURjSmbIDOvF8BACOUnaJBqCXASTxEk4fKa7sxbottiee2M22HZVvghamN7qqNwW-LFzxtl5WqOus8lh7fV7a2n5WWNZ47q4y_QCelrL253Mdz9PE4eR8_R7PXp-n4bhZJTngXxYLGKRPSZKUWqkgzA6lKqVIkYSE3OmNUKlpyooskzmJRcskzWqSsKDOQhJ2jm93ctbNfvfFd3oTzTV3L1tje5yQhRHCaiTRI-U6qnfXemTJfu6qRbpsTyH8A5gFgfgCY7wEG2_V-Q69C7890IBYEsBP82m3v2vDw_zO_ATt9fuY</recordid><startdate>20150910</startdate><enddate>20150910</enddate><creator>Jain, Rama</creator><creator>Mathur, Michelle</creator><creator>Lan, Jiong</creator><creator>Costales, Abran</creator><creator>Atallah, Gordana</creator><creator>Ramurthy, Savithri</creator><creator>Subramanian, Sharadha</creator><creator>Setti, Lina</creator><creator>Feucht, Paul</creator><creator>Warne, Bob</creator><creator>Doyle, Laura</creator><creator>Basham, Stephen</creator><creator>Jefferson, Anne B.</creator><creator>Lindvall, Mika</creator><creator>Appleton, Brent A.</creator><creator>Shafer, Cynthia M.</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150910</creationdate><title>Discovery of Potent and Selective RSK Inhibitors as Biological Probes</title><author>Jain, Rama ; 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| subjects | Animals Cell Line Crystallography, X-Ray Humans Male Mice Models, Molecular Phosphorylation Protein Conformation Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Rats, Sprague-Dawley Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors Signal Transduction Structure-Activity Relationship Y-Box-Binding Protein 1 - metabolism |
| title | Discovery of Potent and Selective RSK Inhibitors as Biological Probes |
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