Editorial [Hot Topic: p38 Kinase Inhibitor (Guest Editor: Katerina Leftheris)]

The last several years have seen an explosion of interest in developing inhibitors to kinases found critical to the pathogenesis of disease. Improvements in screening techniques, surveying kinase selectivity and understanding the side-effects of kinase inhibition have made targeting kinases for therapeutic intervention more attainable. Development of p38α MAP kinase inhibitors for the treatment of inflammatory disease has historically been elusive for several reasons. Different structural classes appeared to have different toxicity profiles both in animal studies and in the clinic. Furthermore, several of the compounds with reported data were determined not to be highly selective for p38α further compounding the issue of whether the toxicities observed were p38α related. Recent advances in our understanding of p38-related mechanisms as well as significant improvements in the ability to screen compounds for kinase selectivity suggest there may be opportunities to overcome these issues. To fully explore recent advances in the p38 field, Current Topics in Medicinal Chemistry has devoted this entire issue to a review of the current chemistry and biology of p38 inhibition. The initial article authored by Gary Schieven from Bristol-Myers Squibb provides a biological background for why p38α kinase activation leads to inflammation at the cellular level and the mechanisms by which p38α regulates gene expression. Donna Dambach from Bristol-Myers Squibb describes potential adverse effects of p38 inhibition as well as what is known though KO mouse technology and published disclosures from clinical trials. Ioana Papa-Burke and her colleagues from Amphora describe the use of microfluidic technology to rapidly screen compounds against a collection of more than 60 kinases enabling a very rapid and accurate identification of multiple scaffolds. David Diller and his colleagues from Pharmacopeia further describe advances in selectivity screening for kinases. John Hynes and K. Leftheris from Bristol-Myers Squibb provide a survey of the p38 kinase inhibitor patent and published literature over the last several years and describe new chemotypes that have been disclosed. Ravi Natarajan and James Doherty from Merck describe the development of novel quinazolinone and associated chemotypes as p38 inhibitors. Steve Wrobleski and Arthur Doweyko from Bristol-Myers Squibb co-authored a review of known X-ray structures of p38 inhibitor-enzyme complexes. They describe the current understanding of structural elements and interactions that may play a role in how p38 inhibitors bind to the enzyme. Finally, David Goldstein and Tobias Gabriel from Roche review ten chemotypes that were selected for development and describe data obtained from clinical trials. With a number of companies in clinical trials with p38 inhibitors, it should become clear in the near future whether this attractive target for suppressing inflammation can lead to a marketed drug for p38- mediated diseases. I would like to express my gratitude the following individuals who served as manuscript reviewers for this issue: J. Das, M. Dhar, A. Dyckman and S. Wrobleski. Finally, I am grateful to all the authors for their timely and well written contributions in what we hope will be an informative contribution to the field.