Discovery and Basic Research
Paul Shapiro, PhD
Professor
University of Maryland School of Pharmacy
Baltimore, Maryland
Alexander Tropsha, PhD
KH Lee Distinguished Professor
University of North Carolina
Chapel Hill, North Carolina
This presentation will present an overview of the discovery of a function-selective small molecule inhibitor of p38α MAP kinase for the treatment of inflammation associated with acute lung injury. Currently available inhibitors of p38 MAP kinases to reduce inflammation have primarily been designed to disrupt ATP binding and block all enzymatic activity. However, none of these compounds have been approved for clinical use due to unwanted toxicity. The lack of clinical success with ATP-competitive inhibitors may be attributed to p38 MAP kinase regulation of dozens of substrates, some of which may have pro- or anti-inflammatory effects. As an alternative, we describe ATP-independent compounds that are designed to inhibit pro-inflammatory p38 MAP kinase functions but preserve anti-inflammatory functions. The preclinical evaluation of the compounds in partnership with a small biotech company and the completion of phase I clinical trial will be discussed.