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

A04 Chemical epigenetics: Inhibitors of methyl-lysine binding proteins

Manfred Jung

Manfred Jung

Principal investigator of

Methyl-lysine readers act as sensors of different histone methylation states and are mediators of epigenetic signalling. We already showed the importance of the reader protein Spindlin1 (Spin1) in oncogenic signalling. We will rationally optimise available inhibitors for Spin1 using structure-guided synthesis. We shall identify new chemotypes and chemical space as lead inhibitors for Spin1. Similar campaigns of assay development, screening, and compound optimisation will be carried out for other methyl-lysine readers.

Selected project-relevant publications

  • Schulz-Fincke J., Hau M., Barth J., Robaa D., Willmann D., Kurner A., Haas J., Greve G., Haydn T., Fulda S., Lubbert M., Ludeke S., Berg T., Sippl W., Schule R. and Jung M. (2017) Structure-activity studies on N-Substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation. Eur J Med Chem 144, 52-67.
  • Schiedel M., Herp D., Hammelmann S., Swyter S., Lehotzky A., Robaa D., Olah J., Ovadi J., Sippl W. and Jung M. (2017) Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals). J Med Chem
  • Hau M., Zenk F., Ganesan A., Iovino N. and Jung M. (2017) Cellular analysis of the action of epigenetics drugs and probes. Epigenetics  12, 308-322.
  • Slynko I., Schmidtkunz K., Rumpf T., Klaeger S., Heinzlmeir S., Najar A., Metzger E., Kuster B., Schule R., Jung M. and Sippl W. (2016) Identification of Highly Potent Protein Kinase C-Related Kinase 1 Inhibitors by Virtual Screening, Binding Free Energy Rescoring, and in vitro Testing. ChemMedChem doi: 10.1002/cmdc.201600284
  • Morera L., Roatsch M., Furst M.C., Hoffmann I., Senger J., Hau M., Franz H., Schule R., Heinrich M.R. and Jung M. (2016) 4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A. ChemMedChem doi: 10.1002/cmdc.201600218
  • Schiedel M., Rumpf T., Karaman B., Lehotzky A., Gerhardt S., Ovadi J., Sippl W., Einsle O. and Jung M. (2016) Structure-Based Development of an Affinity Probe for Sirtuin 2. Angew Chem Int Ed Engl 55, 2252-2256.
  • Roatsch M., Robaa D., Pippel M., Nettleship J.E., Reddivari Y., Bird L.E., Hoffmann I., Franz H., Owens R.J., Schule R., Flaig R., Sippl W. and Jung M. (2016) Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases. Future Med Chem [epub ahead of print]
  • Morera L., Lubbert M. and Jung M. (2016) Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics 8, 57.
  • Metzger E., Willmann D., Mcmillan J., Forne I., Metzger P., Gerhardt S., Petroll K., Von Maessenhausen A., Urban S., 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 KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. Nat Struct Mol Biol 23, 132-139.
  • 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.
  • Gajer J.M., Furdas S.D., Grunder A., Gothwal M., Heinicke U., Keller K., Colland F., Fulda S., Pahl H.L., Fichtner I., Sippl W. and Jung M. (2015) Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo. Oncogenesis 4, e137.
  • 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.