James W. Janetka, Ph.D.

Professor
Biochemistry and Molecular Biophysics
Adjunct Professor
Chemistry

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

  • 314-362-0509

  • 314-362-9299

  • 2602 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 drug design and synthesis for cancer and infectious disease

Research Abstract:

My laboratory is interested in structure-based drug design (SBDD) and synthesis of chemical biology tools useful for cancer and infectious disease. We develop unique small molecular weight ligands and inhibitors of proteins associated with tumor progression and metastasis, bacterial virulence, parasite viability and drug resistance. We rationally design small-molecule, glycoside and peptidomimetic inhibitors utilizing X-ray crystallography, computational and traditional medicinal chemistry approaches then subsequently synthesize and optimize compounds for improved binding affinity, target inhibition, selectivity, cellular potency, pharmacokinetics, and in vivo activity. These targeted compounds are used as chemical tools to aid in deciphering molecular mechanisms important in cancer and infectious disease. One research program is focused on inhibitors of transmembrane 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 regulatory mechanisms of serine proteases and 3) evaluating the role of proteases and their inhibitors on cell signaling, invasion and cancer metastasis. We also have a project directed at novel treatment for COVID-19 using covalent inhibitors of the host cell transmembrane protease TMPRSS2, essential for viral entry and spread. Another large area of research is in developing glycomimetic lectin antagonists. We have several projects including inhibitors of the bacterial adhesin proteins FimH, FmlH, PapG and multiple others in UPEC (uropathogenic E. coli) to develop new anti-virulence therapies for the prevention and treatment of urinary tract infections (UTIs). We also target Shiga toxins, LecA and LecB lectins in Pseudomonas aeruginosa and the Gal/GalNAc lectin/toxin of Entamoeba histolytica (amoeba). A final effort of my group is interested in small novel molecule therapies for parasitic diseases such as nematode and filarial worms, as well as Toxoplasma gondii where we are inhibiting essential kinases and proteases.

Selected Publications:

[1] Tyagi, R., Bulman, C. A., Cho-Ngwa, F., Fischer, C., Marcellino, C., Arkin, M. R., McKerrow, J. H., McNamara, C. W., Mahoney, M., Tricoche, N., Jawahar, S., Janetka, J. W., Lustigman, S., Sakanari, J., and Mitreva, M. (2021) An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease, Pathogens 10.

[2] McLellan, L. K., McAllaster, M. R., Kim, A. S., Tothova, L., Olson, P. D., Pinkner, J. S., Daugherty, A. L., Hreha, T. N., Janetka, J. W., Fremont, D. H., Hultgren, S. J., Virgin, H. W., and Hunstad, D. A. (2021) A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis, PLoS Pathog 17, e1009314.

[3] Damalanka, V. C., Maddirala, A. R., and Janetka, J. W. (2021) Novel approaches to glycomimetic design: development of small molecular weight lectin antagonists, Expert Opin Drug Discov, 1-24.

[4] Yang, B., Hird, A. W., Bodnarchuk, M. S., Zheng, X., Dakin, L., Su, Q., Daly, K., Godin, R., Hattersley, M. M., Brassil, P., Redmond, S., John Russell, D., and Janetka, J. W. (2020) Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2- pyridylmethoxy)benzamide (AZD7254), Bioorg Med Chem 28, 115227.

[5] Janetka, J. W., Hopper, A. T., Yang, Z., Barks, J., Dhason, M. S., Wang, Q., and Sibley, L. D. (2020) Optimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis, J Med Chem 63, 6144-6163.

[6] Tyagi, R., Elfawal, M. A., Wildman, S. A., Helander, J., Bulman, C. A., Sakanari, J., Rosa, B. A., Brindley, P. J., Janetka, J. W., Aroian, R. V., and Mitreva, M. (2019) Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics, Sci Rep 9, 9085.

[7] Maddirala, A. R., Klein, R., Pinkner, J. S., Kalas, V., Hultgren, S. J., and Janetka, J. W. (2019) Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design, J Med Chem 62, 467-479.

[8] Kawaguchi, M., Yamamoto, K., Takeda, N., Fukushima, T., Yamashita, F., Sato, K., Kitamura, K., Hippo, Y., Janetka, J. W., and Kataoka, H. (2019) Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine, Commun Biol 2, 11.

[9] Damalanka, V. C., Wildman, S. A., and Janetka, J. W. (2019) Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin, Medchemcomm 10, 1646-1655.

[10] Damalanka, V. C., Han, Z., Karmakar, P., O'Donoghue, A. J., La Greca, F., Kim, T., Pant, S. M., Helander, J., Klefstrom, J., Craik, C. S., and Janetka, J. W. (2019) Discovery of Selective Matriptase and Hepsin Serine Protease Inhibitors: Useful Chemical Tools for Cancer Cell Biology, J Med Chem 62, 480-490.

Last Updated: 2/16/2021 2:47:37 PM

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