James W. Janetka, Ph.D.

Associate Professor
Biochemistry and Molecular Biophysics

Biochemistry, Biophysics, and Structural Biology Program
Molecular Cell Biology Program
Molecular Microbiology and Microbial Pathogenesis Program

  • 314-362-0509

  • 314-362-9299

  • 8231

  • 2614 Cancer Research Building

  • janetkaj@WUSTL.EDU

  • http://biochem.wustl.edu/janetkaj/

  • protease, kinase, cancer, infection, lectin, chemistry, synthesis, drug discovery, peptidomimetic, inhibitor

  • The rational structure-based ligand design and synthesis of chemical tools useful for studying cancer and infectious disease

Research Abstract:

My laboratory is focused on the rational structure-based ligand design and synthesis of chemical tools useful for studying cancer and infectious disease. My research group develops novel small molecular weight modulators of protein targets associated with tumor development, cancer progression, resistance to chemotherapy, bacterial virulence, and antibiotic resistance. We design small-molecule and peptidomimetic inhibitors utilizing modern computational, synthetic and medicinal chemistry approaches then subsequently optimize hits/compounds for improved binding affinity, target inhibition, selectivity, cellular potency, pharmacokinetics, and in vivo activity. These targeted compounds are then used as chemical tools to aid in deciphering molecular mechanisms important in cancer and infectious disease. The major research in my group is focused on developing active-site directed and allosteric inhibitors of trypsin-like serine proteases such as HGFA (hepatocyte growth factor activator), matriptase and hepsin which are responsible for the activation of growth factors upstream of receptor tyrosine kinase activation and cell signaling. Using the inhibitors we are 1) studying the extracellular regulation of growth factor and kinase activation and 2) elucidating molecular mechanisms of allosteric regulation of serine proteases and 3) evaluating the role of proteases and their inhibitors on cell signaling, invasion and cancer metastasis. Another large area of research in my lab is the rational design of small molecular weight carbohydrate-protein interaction antagonists. In one project we are targeting the bacterial adhesion protein FimH in UPEC (uropathogenic E. coli) in order to develop targeted non-cytotoxic therapies for the prevention, treatment and reduction of antibiotic resistance in recurring UTI. A long-term goal of my research is to develop more effective and innovative therapeutics for the treatment of diseases with large medical need such as metastatic and chemoresistant cancer, as well as chronic, antibiotic resistant microbial infections.

Selected Publications:

Han Z, Pinkner JS, Ford B, Obermann R, Nolan W, Wildman SA, Hobbs D, Ellenberger T, Cusumano CK, Hultgren SJ, Janetka JW. Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists. Journal of Medicinal Chemistry 2010 53: 4779-479.

Oza V, Ashwell S, Brassil P, Breed J, Deng C, Ezhuthachan J, Haye H, Horn C, Janetka J, Lyne P, Newcombe N, Otterbien L, Pass M, Read J, Roswell S, Su M, Toader D, Yu DW, Yu Y, Valentine A, Webborn P, White A, Zabludoff S, Zheng XL. Discovery of a novel class of triazolones as Checkpoint Kinase inhibitors—Hit to lead exploration. Bioorganic & Medicinal Chemistry Letters 2010 20: 5133-5138.

Ma CX, Janetka JW, Piwnica-Worms H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends in Molecular Medicine 2011 17: 88-96.

Cusumano CK, Pinkner JS, Han Z, Greene S, Ford B, Janetka JW, Hultgren SJ. Treatment and Prevention of Urinary Tract Infection with Orally Active Mannoside FimH Inhibitors. Science Translational Medicine 2011 3:109: 1-10.

Han Z, Pinkner JS, Ford B, Chorell E, Crowley JM, Cusumano CK, Campbell S, Henderson JP, Hultgren SJ, Janetka JW. Lead Optimization Studies on FimH Antagonists: Discovery of Potent and Orally Bioavailable Ortho-Substituted Biphenyl Mannosides. Journal of Medicinal Chemistry 2012 55: 3945–3959.

Last Updated: 12/17/2013 10:01:52 AM

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