Mike Bührmann, Dr. rer. nat.

Position: Postdoctoral fellow

Room no.: CP-02-111

Telephone no.: +49 231 755 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 ;-)

Research projects:

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.

 

Publications:

1. Bartolini, D.; Bührmann, M.; Barreca, M. L.; Manfroni, G.; Cecchetti, V.; Rauh, D.; Galli, F.. Co-crystal structure determination and cellular evaluation of 1,4-dihydropyrazolo4,3-c 1,2 benzothiazine 5,5-dioxide p38α MAPK inhibitors. Biochem. Biophys. Res. Com. 2019, 511 (3), 579–586.

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2. a) Bührmann, M.; Hardick, J.; Weisner, J.; Quambusch, L.; Rauh, D.. Covalent Lipid Pocket Ligands Targeting p38α MAPK Mutants. Angew. Chem. Int. Ed. Engl. 2017, 56 (43), 13232–13236.

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   b) Bührmann, M.; Hardick, J.; Weisner, J.; Quambusch, L.; Rauh, D.. Kovalente Liganden zur Adressierung einer lipophilen Bindetasche in der MAPK p38 α. Angew. Chem. 2017, 129 (43), 13415–13419.

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3. Bührmann, M.; Wiedemann, B. M.; Müller, M. P.; Hardick, J.; Ecke, M.; Rauh, D.. Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK. PLoS ONE 2017, 12 (9), e0184627.

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4. Halekotte, J.; Witt, L.; Ianes, C.; Krüger, M.; Bührmann, M.; Rauh, D.; Pichlo, C.; Brunstein, E.; Luxenburger, A.; Baumann, U.; Knippschild, U.; Bischof, J.; Peifer, C.. Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK. Molecules 2017, 22 (4), 522.

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5. Plenker, D.; Riedel, M.; Brägelmann, J.; Dammert, M. A.; Chauhan, R.; Knowles, P. P.; Lorenz, C.; Keul, M.; Bührmann, M.; Pagel, O.; Tischler, V.; Scheel, A. H.; Schütte, D.; Song, Y.; Stark, J.; Mrugalla, F.; Alber, Y.; Richters, A.; Engel, J.; Leenders, F.; Heuckmann, J. M.; Wolf, J.; Diebold, J.; Pall, G.; Peifer, M.; Aerts, M.; Gevaert, K.; Zahedi, R. P.; Buettner, R.; Shokat, K. M.; McDonald, N. Q.; Kast, S. M.; Gautschi, O.; Thomas, R. K.; Sos, M. L.. Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci. Transl. Med 2017, 9 (394).

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6. Walter, N. M.; Wentsch, H. K.; Bührmann, M.; Bauer, S. M.; Döring, E.; Mayer-Wrangowski, S.; Sievers-Engler, A.; Willemsen-Seegers, N.; Zaman, G.; Buijsman, R.; Lämmerhofer, M.; Rauh, D.; Laufer, S. A.. Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine. J. Med. Chem. 2017, 60 (19), 8027–8054.

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7. a) Wentsch, H. K.; Walter, N. M.; Bührmann, M.; Mayer-Wrangowski, S.; Rauh, D.; Zaman, G. J. R.; Willemsen-Seegers, N.; Buijsman, R. C.; Henning, M.; Dauch, D.; Zender, L.; Laufer, S.. Optimized Target Residence Time: Type I1/2 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine. Angew. Chem. Int. Ed. Engl. 2017, 56 (19), 5363–5367.

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   b) Wentsch, H. K.; Walter, N. M.; Bührmann, M.; Mayer-Wrangowski, S.; Rauh, D.; Zaman, G. J. R.; Willemsen-Seegers, N.; Buijsman, R. C.; Henning, M.; Dauch, D.; Zender, L.; Laufer, S.. Optimierte Bindungsdauer am Zielenzym: Typ-I1/2 -Inhibitoren der p38α-MAP-Kinase mit verbesserter Bindungskinetik durch direkte Interaktion mit der R-Spine. Angew. Chem. 2017, 129 (19), 5448–5453.

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