Professor Dr. Manfred Jung
Institute of Pharmaceutical Sciences
Albert-Ludwig-University Freiburg
Germany

Chemical Epigenetics – Chemical Tools to Interrogate Reversible Lysine Acetylation and Methylation

Epigenetics is defined as inheritable changes in the phenotype of a cell or an organism that are regulated by mechanisms other than changes in the DNA sequence. Epigenetic mechanisms respond to external signals, e.g. chemicals, stress or nutrition, and affect transcriptional regulation. Epigenetics may preserve these effects even if the initial stimulus is not present any longer. It may be as stable as a genetic alteration but is still principally reversible. One of the major epigenetic mechanisms is the posttranslational modification of lysine residues in histone proteins which also occurs on other protein substrates.

In this talk the principle mechanisms of epigenetics are introduced, selected epigenetic targets and available inhibitors are presented and studies from our own research on chemical tools to probe reversible histone acetylation and methylation are presented.

Selected references: 

1. Selective Sirt2-inhibition by ligand-induced rearrangement of the active site. T. Rumpf, M. Schiedel, B. Karaman, C. Roessler, B. J. North, A. Lehotzky, J. Olah, K. I. Ladwein, K. Schmidtkunz, M. Gajer, M. Pannek, C. Steegborn, D. A. Sinclair, S. Gerhardt, J. Ovadi, M. Schutkowski, W. Sippl, O. Einsle, M. Jung; Nat. Commun. 6 (2015) 6263.
2. Structure-based development of a Sirtuin 2 affinity probe. M. Schiedel, T. Rumpf, B. Karaman, A. Lehotzky, S. Gerhardt, J. Ovádi, W. Sippl, O. Einsle, M. Jung; Angew. Chem. Int. Ed. 55 (2016) 2252-2256.
3. Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform. T. Wagner, H. Greschik, T. Burgahn, K. Schmidtkunz, A.‑K. Schott, J. McMillan, L. Baranauskienė, Y. Xiong, O. Fedorov, J. Jin, U. Oppermann, D. Matulis, R. Schüle, M. Jung; Nucl. Acids Res. (2016) doi:10.1093/nar/gkw089.
4. Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals). M. Schiedel, D. Herp, S. Hammelmann, S. Swyter, A. Lehotzky, D. Robaa, J. Oláh, J. Ovádi, W. Sippl, M. Jung; J. Med. Chem. (2017) in press.
5. Beyond the BET family: targeting CBP/p300 with 4-acyl pyrroles. M. Hügle, X. Lucas, D. Ostrovskyi, P. Regenass, S. Gerhardt, O. Einsle, M. Hau, M. Jung, B. Breit, S. Günther, D. Wohlwend; Angew. Chem. Int. Ed. (2017) accepted.

Host: Assistant professor Thomas B. Poulsen, PhD, Department of Chemistry, Aarhus University