Mike Bührmann, Dr. rer. nat.
Position: Postdoctoral fellow
Room no.: CP-02-111
Telephone no.: +49 (0)231 755 7054
Member of the group since: 10/2011
University Degree: Dr. rer. nat., Medicinal Chemistry and Chemical Biology, TU Dortmund University
Earlier positions: Bachelor studies in Chemistry and Biology at the University of Bremen; Master studies at Rauh group on synthesis and evaluation of allosteric kinase modulators
Expertise: Organic synthesis, biochemical and -physical methods, protein crystallization
Off-Lab activities: Music: concerts and composing, playing drums and guitar, travelling, games and quizzes: both, as master and apprentice ;-)
The catalytic phosphate transfer in cellular signaling cascades is often considered the primary function of protein kinases. However, functions independent from this mechanism are involved in several biological processes and arrest increasing interest in medicinal chemistry and drug development. Those may include the regulation or localization of kinase substrates via protein-protein interactions or the formation of multi-enzyme complexes, respectively. This is usually realized by addressing alternative binding regions distant from the enzyme’s active site. Hence, the discovery of corresponding binding pockets and the development of small molecules capable of modulating scaffolding functions are of great interest in current scientific research.
This project focused on the further development of previously identified lipid pocket ligands (LiPoLis) binding to a unique pocket in p38α MAPK of yet unknown biological function. A diverse library of both, reversible derivatives addressing the wildtype protein and covalently binding probe molecules targeting tailored p38α mutants harboring an artificially introduced cysteine residue, were designed and synthesized. Thorough characterization methods comprised SPR, MST, BLI and thermal shift assays as well as MS and MS/MS experiments. Novel co-crystal structures substantiated the initial structure-based designs and will pave the way for future cellular studies to elucidate the biological role of the p38α lipid pocket.
- a) M. Bührmann, J. Hardick, J. Weisner, L. Quambusch and D. Rauh, “Covalent Lipid Pocket Ligands Targeting p38α MAPK Mutants”, Angewandte Chemie International Edition (2017), 56(43), 13232-13236. b) M. Bührmann, J. Hardick, J. Weisner, L. Quambusch und D. Rauh, “Kovalente Liganden zur Adressierung einer lipophilen Bindetasche in der MAPK p38α“, Angewandte Chemie (2017), 129(43), 13415-13419.
- M. Bührmann, B.W. Wiedemann, M.P. Müller, J. Hardick, M. Ecke and D. Rauh, “Structure-Based Design, Synthesis and Crystallization of 2-Arylquinazolines as Lipid Pocket Ligands of p38α MAPK”, PLoS ONE (2017), 12(9): e0184627.
- a) H.K. Wentsch*, N.M. Walter*, M. Bührmann*, S.C. Mayer-Wrangowski, D. Rauh, G.J.R. Zaman, N. Willemsen-Seegers, R.C. Buijsman, M. Henning, D. Dauch, L. Zender and S.A. Laufer, “Optimized Target Residence Time: Type I½ Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine”, Angewandte Chemie International Edition (2017), 56(19), 5363-5367. b) H.K. Wentsch*, N.M. Walter*, M. Bührmann*, S.C. Mayer-Wrangowski, D. Rauh, G.J.R. Zaman, N. Willemsen-Seegers, R.C. Buijsman, M. Henning, D. Dauch, L. Zender und S.A. Laufer, “Optimierte Bindungsdauer am Zielenzym: Typ I½-Inhibitoren der p38α-MAP-Kinase mit verbesserter Bindungskinetik durch direkte Interaktion mit der R-Spine“, Angewandte Chemie (2017), 129(19), 5448-5453.
- N.M. Walter*, H.K. Wentsch*, M. Bührmann*, S.M. Bauer, E. Döring, S.C. Mayer-Wrangowski, A. Sievers-Engler, N. Willemsen-Seegers, G.J.R. Zamar, R.C. Buijsman, D. Rauh, M. Lämmerhofer and S.A. Laufer, “Design, Synthesis and Biological Evaluation of Novel Type I½ p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency and Prolonged Target Residence Time by Interfering with the R-Spine”, Journal of Medicinal Chemistry (2017), 60(19), 8027-8054.
- J. Halekotte*, L. Witt, C. Ianes*, M. Krüger, M. Bührmann, D. Rauh, C. Pichlo, E. Brunstein, A. Luxenburger, U. Baumann, U. Knappschild, J. Bischof and C. Peifer, “Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK”, Molecules (2017), 22(4), 522-559.
- D. Plenker*, M. Riedel*, J. Brägelmann, M.A. Dammert, R. Chauhan, R.P. Knowles, C. Lorenz, M. Keul, M. Bührmann, O. Pagel, V. Tischler, A.H. Scheel, D. Schütte, Y. Song, J. Stark, F. Mrugalla, Y. Alber, A. Richters, J. Engel, F. Leeders, J.M. Heuckmann, J. Wolf, J. Diebold, G. Pall, M. Peifer, M. Aerts, K. Gevaert, R.P. Zahedi, R. Buettner, K.M. Shokat, N.Q. McDonald, S.M. Kast, O. Gautschi, R.K. Thomas and M.L. Sos, “Drugging the Catalytically Inactive State of RET Kinase in RET-Rearranged Tumors”, Science Translational Medicine (2017), 9(394): eaah6144.