title: Discovery and Characterization of a Biologically Active Non-ATP-Competitive p38 MAP Kinase Inhibitor.
abstract: Mitogen-activated protein kinase (MAPK) p38 is part of a broad and ubiquitously expressed family of MAPKs 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 and has been 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 adenosine triphosphate (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 that is both non-ATP competitive and biologically active in cell-based models for p38 activity. This is the first reported discovery of a non-ATP-competitive 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 non-ATP-competitive inhibitors of p38 activity.
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
authors.forename: Brice A P
authors.initials: BA
authors.lastname: Wilson
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Muhammad S
authors.initials: MS
authors.lastname: Alam
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
authors.forename: Tad
authors.initials: T
authors.lastname: Guszczynski
authors.affiliation: Department of Biochemistry, Faculty of Chemistry, Wrocław University of Technology, Wrocław, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Jakob
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Shilpa R
authors.initials: SR
authors.lastname: Shenoy
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
authors.forename: Carter A
authors.initials: CA
authors.lastname: Mitchell
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA Data Management Services, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Ekaterina I
authors.initials: EI
authors.lastname: Goncharova
authors.affiliation: Data Management Services, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Evans
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua-Peking Center for Life Sciences and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Frederick, MD, USA okeefeba@mail.nih.gov.
authors.forename: Barry R
authors.initials: BR
authors.lastname: O'Keefe
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases
keywords: enzyme kinetics; high throughput; non–ATP competitive; p38