Protein kinases are enzymes with remarkable domain plasticity that plays a key role not only in their regulation but also in the mode of action of inhibitors and drugs targeting these dynamic systems. In this presentation I will outline some of the challenges targeting conformational states of kinases as well as new opportunities for drug discovery. I will present structure based design strategies for the development of highly selective inhibitors and consequences targeting different activation states of kinases interfering with scaffolding function. In addition, the importance of target residency, structural mechanisms leading to slow off-rates and methods measuring these parameters in cellular systems will be discussed.
References:
- Chaikuad, A., E, M.C.T., Zimmer, J., Liang, Y., Gray, N.S., Tarsounas, M., and Knapp, S. (2014). A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. Nature Chemical Biology 10, 853-860.
- Muller, S., Chaikuad, A., Gray, N.S., and Knapp, S. (2015). The ins and outs of selective kinase inhibitor development. Nature chemical biology 11, 818-821.
- Chaikuad, A., Koch, P., Laufer, S.A., and Knapp, S. (2018). The Cysteinome of Protein Kinases as a Target in Drug Development. Angew Chem Int Ed Engl 57, 4372-4385.
- Georgi, V., Schiele, F., Berger, B.T., Steffen, A., Marin Zapata, P.A., Briem, H., Menz, S., Preusse, C., Vasta, J.D., Robers, M.B., et al. (2018). Binding Kinetics Survey of the Drugged Kinome. J Am Chem Soc 140, 15774-15782.
- Heroven, C., Georgi, V., Ganotra, G.K., Brennan, P., Wolfreys, F., Wade, R.C., Fernandez-Montalvan, A.E., Chaikuad, A., and Knapp, S. (2018). Halogen-Aromatic pi Interactions Modulate Inhibitor Residence Times. Angew Chem Int Ed Engl 57, 7220-7224.
- Vasta, J.D., Corona, C.R., Wilkinson, J., Zimprich, C.A., Hartnett, J.R., Ingold, M.R., Zimmerman, K., Machleidt, T., Kirkland, T.A., Huwiler, K.G., et al. (2018). Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement. Cell Chem Biol 25, 206-214 e211.
31 maggio
The seminar will be held by Prof. Stefan Knapp of the Institute for Pharmaceutical Chemistry Johann Wolfgang Goethe-Universität,Frankfurt am Main, Germany, in room C (building CU010) at 12:00.