Target engagement analysis and link to pharmacodynamic endpoint for a novel class of CNS-penetrant and efficacious p38α MAPK inhibitors

Adam D. Bachstetter, D. Martin Watterson, Linda J. Van Eldik*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

12 Scopus citations

Abstract

The protein kinase, p38α MAPK, is a key intracellular transducer of stressor-induced neuroinflammatory responses and, as such, is of high interest as a potential therapeutic target. We recently reported the synthesis and evaluation of first-in-class CNS-penetrant and highly specific p38 MAPK inhibitors that avoid target crossover issues seen in popular small molecule p38 MAPK inhibitors used in hundreds of previous reports. The novel p38 MAPK inhibitors, represented in this study by MW181, are efficacious in vivo. Pharmacodynamic actions include attenuation of stressor-induced increases in brain proinflammatory cytokine levels. We report here more detailed analyses of MW181 target engagement and specific linkage to the downstream increase in glia proinflammatory cytokine production. In vivo validation included demonstration that oral administration of MW181 suppresses lipopolysaccharide-induced increases in mouse brain IL-1β, TNFα, IL-6, IL-10, and CXCL1 but not in a drug-resistant p38α MAPK mutant mouse.

Original languageEnglish (US)
Pages (from-to)454-460
Number of pages7
JournalJournal of Neuroimmune Pharmacology
Volume9
Issue number4
DOIs
StatePublished - Sep 2014

Keywords

  • Cytokine
  • Drug discovery
  • Microglia
  • Mitogen-activated protein kinase
  • Neurodegeneration
  • Signal transduction

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Fingerprint Dive into the research topics of 'Target engagement analysis and link to pharmacodynamic endpoint for a novel class of CNS-penetrant and efficacious p38α MAPK inhibitors'. Together they form a unique fingerprint.

Cite this