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John Schindler, Ph.D.Research Assistant Professor
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Office: Cancer Research Building
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Research
We are presently studying two proteins that are involved in inflammatory diseases. One of our current projects is focused on applying “kinetic targeted guided synthesis” for the discovery of interfacial inhibitors for the protein kinases p38α and MK2. Using this approach, we propose to discover p38 inhibitors that selectively block the phosphorylation of MK2, which is a key substrate involved in the biosynthesis of the pro-inflammatory cytokine TNFα. By selectively targeting the inhibition of MK2 we will block the production of TNFα, but spare the function of other p38α substrates that are involved in critical cell functions and feedback mechanisms. In addition to this project we are also studying the signaling mechanism of macrophage migration inhibitory factor (MIF). Our overall goal in this project is to determine the binding interface between MIF and its cell-surface receptor, CD74. Characterization of the MIF:CD74 interaction will ultimately lead to a better design of small molecule inhibitors, which can be used as tools to elucidate this signaling pathway.
Most Recent Publications
- Selness, S.R., Boehm, T.L., Walker, J.K., Devadas, B., Durley, R.C., Kurumbail, R., Shieh, H., Xing, L., Hepperle, M., Rucker, P.V., Jerome, K.D., Benson, A.G., Marrufo, L.D., Madsen, H.M., Hitchcock, J., Owen, T.J., Christie, L., Promo, M.A., Hickory, B.S., Alvira, E., Naing, W., Blevis-Bal, R., Devraj, R.V., Messing, D., Schindler, J.F., Hirsch, J., Saabye, M., Bonar, S., Webb, E., Anderson, G. and Monahan, J.B. Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase. Bioorg Med Chem Lett. 21:4059-4065 (2011) [Abstract]
- Mourey, R.J., Burnette, B.L., Brustkern, S.J., Daniels, J.S., Hirsch, J.L., Hood, W.F., Meyers, M.J., Mnich, S.J., Pierce, B.S., Saabye, M.J., Schindler, J.F., South, S.A., Webb, E.G., Zhang, J. and Anderson, D.R. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J Pharmacol Exp Ther 333:797-807 (2010). [Abstract]
- Baima, E.T., Guzova, J.A., Mathialagan, S., Nagiec, E.E., Hardy, M.M., Song, L.R., Bonar, S.L., Weinberg, R.A., Selness, S.R., Woodard, S.S., Chrencik, J., Hood, W.F., Schindler, J.F., Kishore, N. and Mbalaviele, G. Novel insights into the cellular mechanisms of the anti-inflammatory effects of NF-kappaB essential modulator binding domain peptides. J Biol Chem. 285:13498-506 (2010). [Abstract]
- Hall, T., Emmons, T.L., Chrencik, J.E., Gormley, J.A., Weinberg, R.A., Leone, J.W., Hirsch, J.L., Saabye, M.J., Schindler, J.F., Day, J.E., Williams, J.M., Kiefer, J.R., Lightle, S.A., Harris, M.S., Guru, S., Fischer, H.D. and Tomasselli, A.G. Expression, purification, characterization and crystallization of non- and phosphorylated states of JAK2 and JAK3 kinase domain. Protein Expr Purif 69:54-63. (2010). [Abstract]
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Hope, H.R., Anderson, G.D., Burnette, B.L., Compton, R.P., Devraj, R.V., Hirsch, J.L., Keith, R.H., Li, X., Mbalaviele, G., Messing, D.M., Saabye, M.J., Schindler, J.F., Selness, S.R., Stillwell, L.I., Webb, E.G., Zhang, J. and Monahan, J.B.
Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation. J Pharmacol Exp Ther 331:882-95 (2009). [Abstract] - Xing, L., Shieh, H.S., Selness, S.R., Devraj, R.V., Walker, J.K., Devadas, B., Hope, H.R., Compton, R.P., Schindler, J.F., Hirsch, J.L., Benson, A.G., Kurumbail, R.G., Stegeman, R.A., Williams, J.M., Broadus, R.M., Walden, Z. and Monahan, J.B. Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804. Biochemistry 48:6402-11 (2009). [Abstract]