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  • Z01
    • Backofen
    • Manke
  • Z02
    • Breit
    • Einsle
    • Günther
  • Z03 Central tasks

Z02 Epigenetic drug design: Protein crystallography and inhibitor synthesis

Bernhard Breit

Bernhard Breit

Principal investigator of
Oliver Einsle

Oliver Einsle

Principal investigator of
Stefan Günther

Stefan Günther

Principal investigator of

The development of high-affinity inhibitors with potential application in clinical therapy involves a structured process of identifying target proteins and lead structures for inhibitory compounds. Such leads are then optimized in iterative rounds of chemical modification, structural analysis and functional assays. The Z02 core facility provides the CRC with the know-how and equipment to scale-up protein production, identify and validate suitable target proteins, obtain three-dimensional structures, find candidate compounds and optimize leads for ligand screening and protein crystallization.

Selected project-relevant publications

  • Ostrovskyi D., Rumpf T., Eib J., Lumbroso A., Slynko I., Klaeger S., Heinzlmeir S., Forster M., Gehringer M., Pfaffenrot E., Bauer S.M., Schmidtkunz K., Wenzler S., Metzger E., Kuster B., Laufer S., Schule R., Sippl W., Breit B. and Jung M. (2016) Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1). Future Med Chem 8, 1537-1551.
  • Metzger, E., Willmann, D., McMillan, J., Forne, I., Petroll, K., Metzger, P., Gerhardt, S., Maessenhausen, A., Schott, A-K., Espejo, A., Eberlin, A., Wohlwend, D., Schule, K.M., Schleicher, M., Perner, S., Bedford, M.T., Jung, M., Dengjel, J., Flaig, R., Imhof, A., Einsle, O. and Schule, R. (2016) Assembly of methylated LSD1 and CHD1 drives AR-dependent transcription and translocation. Nat Struct Mol Biol, 132-9.
  • Hugle M., Lucas X., Weitzel G., Ostrovskyi D., Breit B., Gerhardt S., Schmidtkunz K., Jung M., Schule R., Einsle O., Gunther S. and Wohlwend D. (2016) Preparation data of the bromodomains BRD3(1), BRD3(2), BRD4(1), and BRPF1B and crystallization of BRD4(1)-inhibitor complexes. Data Brief 7, 1370-1374.
  • Hugle M., Lucas X., Weitzel G., Ostrovskyi D., Breit B., Gerhardt S., Einsle O., Gunther S. and Wohlwend D. (2016) 4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1). J Med Chem 59, 1518-1530
  • Tam H.K., Harle J., Gerhardt S., Rohr J., Wang G., Thorson J.S., Bigot A., Lutterbeck M., Seiche W., Breit B., Bechthold A. and Einsle O. (2015) Structural characterization of O- and C-glycosylating variants of the landomycin glycosyltransferase LanGT2. Angew Chem Int Ed Engl 54, 2811-2815.
  • Rumpf T., Schiedel M., Karaman B., Roessler C., North B.J., Lehotzky A., Olah J., Ladwein K.I., Schmidtkunz K., Gajer M., Pannek M., Steegborn C., Sinclair D.A., Gerhardt S., Ovadi J., Schutkowski M., Sippl W., Einsle O. and Jung M. (2015) Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun 6, 6263.
  • Pritzius A.B. and Breit B. (2015) Asymmetric rhodium-catalyzed addition of thiols to allenes: synthesis of branched allylic thioethers and sulfones. Angew Chem Int Ed Engl 54, 3121-3125.
  • Haydl A.M., Xu K. and Breit B. (2015) Regio- and enantioselective synthesis of N-substituted pyrazoles by rhodium-catalyzed asymmetric addition to allenes. Angew Chem Int Ed Engl 54, 7149-7153.
  • Slynko I., Scharfe M., Rumpf T., Eib J., Metzger E., Schule R., Jung M. and Sippl W. (2014) Virtual screening of PRK1 inhibitors: ensemble docking, rescoring using binding free energy calculation and QSAR model development. J Chem Inf Model 54, 138-150.
  • Gilsbach R., Preissl S., Gruning B.A., Schnick T., Burger L., Benes V., Wurch A., Bonisch U., Gunther S., Backofen R., Fleischmann B.K., Schubeler D. and Hein L. (2014) Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease. Nat Commun 5, 5288.
  • Stolfa D.A., Einsle O., Sippl W. and Jung M. (2012) Current trends in epigenetic drug discovery. Future Med Chem 4, 2029-2037.