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Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2

2014; Elsevier BV; Volume: 24; Issue: 12 Linguagem: Inglês

10.1016/j.bmcl.2014.04.068

1464-3405

James F. Blake, John J. Gaudino, Jason De Meese, Peter Mohr, Mark J. Chicarelli, Hongqi Tian, Rustam Garrey, Allen A. Thomas, Christopher S. Siedem, Michael B. Welch, Gabrielle R. Kolakowski, Robert Kaus, Michael Burkard, Matthew Martinson, Huifen Chen, Brian Dean, Danette A. Dudley, Stephen E. Gould, Patrícia Pacheco, Sheerin Shahidi-Latham, Weiru Wang, Kristina West, Jianping Yin, John G. Moffat, Jacob B. Schwarz,

Protein Kinase Regulation and GTPase Signaling

The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.