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p38 MAP kinase inhibitors: many are made, but few are chosen

Celia Dominguez1, David A Powers, Nuria Tamayo

  • 1Amgen Inc, Chemistry Research & Discovery, Medicinal Chemistry, One Amgen Center Drive, MS 29-1-B, Thousand Oaks, CA 91320-179, USA. celiad@amgen.com

Current Opinion in Drug Discovery & Development
|July 19, 2005
PubMed

Insights

Mitogen-activated protein kinase (MAPK) p38alpha inhibitors, like AMG-548, are being developed to treat inflammatory diseases. Clinical trials show their potential for modulating cytokine production in patients.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Immunology

Background:

  • Mitogen-activated protein kinase (MAPK) p38 is a critical Ser/Thr kinase with four isoforms (p38alpha, p38beta, p38gamma, p38delta).
  • p38alpha is involved in the biosynthesis of pro-inflammatory cytokines TNF-alpha and IL-1beta.
  • MAPK p38alpha integrates inflammatory signaling pathways, making it a key therapeutic target.

Purpose of the Study:

  • To provide an overview of the discovery and development of AMG-548, a selective p38alpha inhibitor.
  • To present pharmacodynamic effects of AMG-548 from a first-in-human study.
  • To discuss other p38alpha inhibitors in clinical trials for inflammatory conditions.

Main Methods:

  • Review of the development of p38alpha inhibitors.
  • Analysis of pharmacodynamic data from a first-in-human study of AMG-548.
  • Summary of clinical trial progress for other p38alpha inhibitors.

Main Results:

  • AMG-548 is a selective and efficacious p38alpha inhibitor.
  • Data from a phase I multidose clinical trial of AMG-548 are presented.
  • Several other p38alpha inhibitors have advanced to clinical trials.

Conclusions:

  • p38alpha inhibitors represent a promising therapeutic strategy for inflammatory diseases.
  • AMG-548 and other agents show potential in modulating cytokine production.
  • Ongoing clinical trials will further define the role of p38alpha inhibition in treating inflammation.

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