Epigenetic drug design: hit identification, lead optimisation, and target validation

Project Summary

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 optimised 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 optimise leads for ligand screening and protein crystallisation.

Selected project-relevant publications

• Warstat R., Pervaiz M., Regenass P., Amann M., Schmidtkunz K., Einsle O., Jung M., Breit B., Hügle M. and Günther S. (2023) A novel pan-selective bromodomain inhibitor for epigenetic drug design. Eur J Med Chem 249, 115139.
• Luise C., Robaa D., Regenass P., Maurer D., Ostrovskyi D., Seifert L., Bacher J., Burgahn T., Wagner T., Seitz J., Greschik H., Park K.S., Xiong Y., Jin J., Schüle R., Breit B., Jung M. and Sippl W. (2021) Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors. Int J Mol Sci 22, doi 10.3390/ijms22115910.
• Wössner N., Alhalabi Z., González J., Swyter S., Gan J., Schmidtkunz K., Zhang L., Vaquero A., Ovaa H., Einsle O., Sippl W. and Jung M. (2020) Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD(+) Dependent Lysine Deacetylases. Front Oncol 10, 657.
• Hügle M., Regenass P., Warstat R., Hau M., Schmidtkunz K., Lucas X., Wohlwend D., Einsle O., Jung M., Breit B. and Günther S. (2020) 4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines. J Med Chem 63, 15603-15620.
• Li J., Moumbock A.F.A. and Günther S. (2020) Exploring Cocrystallized Aromatic Cage Binders to Target Histone Methylation Reader Proteins. J Chem Inf Model 60, 5225-5233.
• Schiedel M., Lehotzky A., Szunyogh S., Oláh J., Hammelmann S., Wössner N., Robaa D., Einsle O., Sippl W., Ovádi J. and Jung M. (2020) HaloTag-Targeted Sirtuin-Rearranging Ligand (SirReal) for the Development of Proteolysis-Targeting Chimeras (PROTACs) against the Lysine Deacetylase Sirtuin 2 (Sirt2). Chembiochem, doi: 10.1002/cbic.202000351.
• Metzger E., Wang S., Urban S., Willmann D., Schmidt A., Offermann A., Allen A., Sum M., Obier N., Cottard F., Ulferts S., Preca B.T., Hermann B., Maurer J., Greschik H., Hornung V., Einsle O., Perner S., Imhof A., Jung M. and Schule R. (2019) KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nat Struct Mol Biol 26, 361-371.
• Sippel D., Rohde M., Netzer J., Trncik C., Gies J., Grunau K., Djurdjevic I., Decamps L., Andrade S.L.A. and Einsle O. (2018) A bound reaction intermediate sheds light on the mechanism of nitrogenase. Science 359, 1484-1489.
• Parnell A.E., Mordhorst S., Kemper F., Giurrandino M., Prince J.P., Schwarzer N.J., Hofer A., Wohlwend D., Jessen H.J., Gerhardt S., Einsle O., Oyston P.C.F., Andexer J.N. and Roach P.L. (2018) Substrate recognition and mechanism revealed by ligand-bound polyphosphate kinase 2 structures. Proc Natl Acad Sci U S A 115, 3350-3355.
• Pervaiz M., Mishra P. and Gunther S. (2018) Bromodomain Drug Discovery – the Past, the Present, and the Future. Chem Rec 18, 1808-1817.
• Mishra P. and Gunther S. (2018) New insights into the structural dynamics of the kinase JNK3. Sci Rep 8, 9435.
• Zhang L., Trncik C., Andrade S.L.A. and Einsle O. (2017) The flavinyl transferase ApbE of Pseudomonas stutzeri matures the NosR protein required for nitrous oxide reduction. Biochim Biophys Acta Bioenerg 1858, 95-102.
• Hugle M., Lucas X., Ostrovskyi D., Regenass P., Gerhardt S., Einsle O., Hau M., Jung M., Breit B., Gunther S. and Wohlwend D. (2017) Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles. Angew Chem Int Ed Engl 56, 12476-12480.
• 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.