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

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

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2635-2639
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number12
DOIs
StatePublished - Jun 15 2014

Keywords

  • Erk2 kinase inhibitors
  • Mek resistance
  • Structure based drug design

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Blake, J. F., Gaudino, J. J., De Meese, J., Mohr, P., Chicarelli, M., Tian, H., Garrey, R., Thomas, A., Siedem, C. S., Welch, M. B., Kolakowski, G., Kaus, R., Burkard, M., Martinson, M., Chen, H., Dean, B., Dudley, D. A., Gould, S. E., Pacheco, P., ... Schwarz, J. B. (2014). Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2. Bioorganic and Medicinal Chemistry Letters, 24(12), 2635-2639. https://doi.org/10.1016/j.bmcl.2014.04.068