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Discovery and characterization of a biologically active noncompetitive p38 MAP kinase inhibitor

Friday, September 18, 2015 — Poster Session V

2:00 p.m. – 3:30 p.m.
FAES Terrace
NCI
PHARM-11

Authors

  • BAP Wilson
  • MS Alam
  • T Guszczynski
  • JD Ashwell
  • BR O'Keefe

Abstract

Mitogen-activated protein kinase (MAPK) p38 is part of a broad and ubiquitously expressed family of MAPK’s whose activity is responsible for mediating an intracellular response to extracellular stimuli through a phosphorylation cascade. p38 is central to this signaling node and is activated by upstream kinases while being responsible for activating downstream kinases and transcription factors via phosphorylation. Dysregulated p38 activity is associated with numerous autoimmune disorders as well as being implicated in the progression of several types of cancer. A number of p38 inhibitors have been tested in clinical trials with none receiving regulatory approval. One characteristic shared by all of the compounds that failed clinical trials is that they are all ATP competitive p38 inhibitors. Seeing this lack of mechanistic diversity as an opportunity, we screened ~32,000 substances in search of novel p38 inhibitors. Among the inhibitors discovered is a compound with nanomolar in-vitro potency (Ki) that is both noncompetitive and biologically active in a cell-based model for p38 activity. This is the first reported discovery of a noncompetitive p38 inhibitor that is active in cells and as such, may enable new pharmacophore designs for both therapeutic and basic research to better understand and exploit noncompetitive inhibitors of p38 activity.

Category: Molecular Pharmacology