James W. Janetka

James W. Janetka, Ph.D.

Associate Professor
Biochemistry and Molecular Biophysics
Lab Website
Publications (link to PubMed Central)
 

 
 

 

Office: 2614 Cancer Research
Phone: 314-362-0509
Email: janetkaj at biochem.wustl.edu

Research

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 identify/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. A main interest in our group is to develop selective inhibitors of serine proteases such as HGFA which is responsible for the activation of HGF and MSP growth factors upstream of oncogenic c-MET and RON receptor tyrosine kinase signaling. Using these inhibitors we are 1) studying the extracellular regulation of growth factor and kinase activation and 2) elucidating the cellular effects of serine protease inhibition on downstream cell signaling and cancer metastasis, and 3) studying the allosteric regulation of proteases. Another broad area of interest is the rational design of carbohydrate-protein interaction antagonists. In one project we are targeting the bacterial adhesion protein FimH in E. coli in order to develop targeted non-cytotoxic therapies for the prevention, treatment and reduction of antibiotic resistance in recurring UTI. A third research interest is the structure-based ligand design of protein-protein interactions which are important in regulating cell signaling and DNA damage/repair. My group also collaborates on many projects with other PIs in order to help design, synthesize and optimize small molecule and peptides as chemical tools for their research programs. A long-term goal of my research is to deliver innovative therapeutics for the treatment of diseases for which there is a very high unmet medical need such as metastatic cancer, chemoresistant cancer, and recurring/resistant infections.

Janetka lab research

Most Recent Publications

  • Han, Z., Harris, P.K.W., Jones, D.E., Chugani, R., Kim, T., Agarwal, M., Shen, W., Wildman, S.A. and Janetka, J.W. Inhibitors of HGFA, matriptase and hepsin serine proteases: A non-kinase strategy to block cell signaling in cancer. ACS Med. Chem. Lett. (E-pub ahead of print.) (2014). [Abstract]
  • Totsika, M., Kostakioti, M., Hannan, T.J., Upton, M., Beaton, S.A., Janetka, J.W., Hultgren, S.J. and Schembri, M.A. A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug resistant uropathogenic Escherichia coli ST131. J Infec Dis 208:921-928 (2013). [Abstract]

  • Guiton, P.S., Cusumano, C.K., Kline, K.A., Dodson, D.W., Han, Z., Janetka, J.W., Henderson, J.P., Caparon, M.G. and Hultgren, S.J. Combination small molecular therapy prevents uropathogenic Escherichia coli cather-associated urinary tract infections in mice. Antimicrob Agents Chemother. 56:4738-4745 (2012). [Abstract]

  • Kostakioti, M., Hadjifrangiskou, M., Cusumano, C.K., Hannan, T.J., Janetka, J.W. and Hultgren, S.J. Distinguishing the contribution of type 1 pili from that of other QseB-misregulated factors when QseC is absent during urinary tract infection. Infect Immun 80:2826-2834 (2012). [Abstract]
  • Oza, V.B., Ashwell, S., Almeida, L., Brassil, P., Bree, J., Deng, C., Gero, T., Grondine, M., Horn, C., Ioannidis, S., Liu, D., Lyne, P.D., Newcombe, N., Pass, M., Read, J., Ready, S., Rowsell, S., Su, M., Toader, D., Vasbinder, M., Yu, D., Yu, Y., Xue, Y., Zabludoff, S. and Janetka, J.W. Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure based design and optimization of thiophene carboxamide ureas. Journal of Medicinal Chemistry 55:5130-5142 (2012). [Abstract]
  • Yang, B., Hird, A.W., Russell, D.J., Fauber, B.P., Dakin, L.A., Zheng, X., Su, Q., Godin, R., Brassil, P., Devereaux, E. and Janetka, J.W. Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO. Bioorganic & Medicinal Chemistry Letters 22:4907-4911 (2012). [Abstract]
  • Han, Z., Pinkner, J.S., Ford, B., Chorell, E., Crowley, J.M., Cusumano, C.K., Campbell, S., Henderson, J.P., Hultgren, S.J. and Janetka, J.W. Lead optimization studies on FimH antagonists: Discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides. Journal of Medicinal Chemistry 55:3945-3959 (2012). [Abstract]
  • Cusumano, C.K., Pinkner, J.S., Han, Z., Greene, S.E., Ford, B.A., Crowley, J.R., Henderson, J.P., Janetka, J.W. and Hultgren, S.J. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Science Translational Medicine 3:1-10 (2011). [Abstract]
  • Ma, C.X., Janetka, J.W. and Piwnica-Worms, H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends in Molecular Medicine 17:88-96 (2011). [Abstract]
  • 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., u, D., Yu, Y., Valentine, A., Webborn, P., White, A., Zabludoff, S. and Zheng, X. Discovery of a novel class of triazolones as checkpoint kinase inhibitors – Hit to lead exploration. Bioorganic & Medicinal Chemistry Letters 20:5133-5138 (2010). [Abstract]
  • Han, Z., Pinkner, J.S., Ford, B., Obermann, R., Nolan, W., Wildman, S.A., Hobbs, D., Ellenberger, T., Cusumano, C.K., Hultgren, S.J. and Janetka, J.W. Structure-based drug design and optimization of mannoside bacterial FimH antagonists. J Med Chem 53:4779-4792 (2010). [Abstract]
  • Aronov, A.A., Tang, Q., Martinez-Botella,G., Bemis, G.W., Cao, J., Chen, G., Ewing, N.P., Ford, P.J., Germann, U.A., Green, J., Hale, M.R., Jacobs, M., Janetka, J.W., Maltais, F., Markland, W., Namchuk M.N., Nanthakumar, S., Poondru, S., Straub, J., ter Haar, E. and Xie, X. Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. J Medicinal Chemistry 52:6362-6368 (2009). [Abstract]
  • Janetka, J.W., Almeida, L., Ashwella, S., Brassil, P.J., Daly, K., Deng C., Gero, T., Glynn, R.E., Horn, C.L., Ioannidis, S., Lyne, P., Newcombe, N.J., Oza, V.B., Pass, M., Springer, S.K., Su, M., Toader, D., Vasbinder, M.M., Yu, D., Yu, Y. and Zabludoff, S.D. Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors. Bioorganic & Medicinal Chemistry Letters 18:4242-4248 (2008). [Abstract]

  • Zabludoff, S.D., Deng C., Grondine, M.R., Sheehy, A.M., Ashwell, S., Cale, B.L., Green, S., Haye, H.R., Horn, C.L., Janetka, J.W., Liu, D., Mouchet, E., Ready, S., Rosenthal, J.L., Queva, C., Schwartz, G.K., Taylor, K.J., Tse, A.N., Walker, G.E., and White, A.M. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Molecular Cancer Therapeutics 7:2955-2966 (2008). [Abstract]
  • Kim, I.J., Ullrich, T., Janetka, J.W., Coop, A., Furness, M.S., Jacobson, A.E., Rothman, R.B., Baumann, M.H., Dersch, C.M., Flippen-Anderson, J.L., George, C. and Rice, K.C. Diaryldimethylpiperazine ligands with μ- and σ-opioid receptor affinity. Synthesis of (+)-4-[(αR)-α-(4-Allyl-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide and (-)-4-[(αR)-α-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide. Bioorganic and Medicinal Chemistry 11:4761-4768 (2003). [Abstract]
  • Janetka, J.W., Raman, P., Satyshur, K.A., Flentke, G.R. and Rich, D.H. Novel cyclic biphenyl ether peptide Β-strand mimetics and HIV-protease inhibitors. J Am Chem Soc 119:441-442 (1997). [Abstract]