Chemical Epigenetics – Inhibitors of histone methyltransferases

Project Summary

Histone methylation is a crucial epigenetic event, involved in many pathological processes. In collaboration with B01 (Schüle) we characterised two new lysine methyltransferases (KMTs), named KMT9 and KMT10. In the next funding period we propose to set up a comprehensive assay platform for KMT9 and KMT10 including assays for cellular target engagement. The proposed work will greatly advance the knowledge on KMT9 and KMT10 function in physiology and pathology and uncover their potential in drug development.

Selected project-relevant publications

• Kohr M., Papenkordt N., Jung M. and Kazmaier U. (2023) Total synthesis and biological evaluation of histone deacetylase inhibitor WF-3161. Org Biomol Chem 21, 4382-4387.
• 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.
• Vogelmann A., Schiedel M., Wössner N., Merz A., Herp D., Hammelmann S., Colcerasa A., Komaniecki G., Hong J.Y., Sum M., Metzger E., Neuwirt E., Zhang L., Einsle O., Groß O., Schüle R., Lin H., Sippl W. and Jung M. (2022) Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration. RSC Chemical Biology doi: 10.1039/D1031CB00244A.
• Vogelmann A., Jung M., Hansen F.K. and Schiedel M. (2022) Comparison of Cellular Target Engagement Methods for the Tubulin Deacetylases Sirt2 and HDAC6: NanoBRET, CETSA, Tubulin Acetylation, and PROTACs. ACS Pharmacol Transl Sci 5, 138-140.
• 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.
• Vogelmann A., Robaa D., Sippl W. and Jung M. (2020) Proteolysis targeting chimeras (PROTACs) for epigenetics research. Curr Opin Chem Biol 57, 8-16.
• Reiner D., Seifert L., Deck C., Schüle R., Jung M. and Stark H. (2020) Epigenetics meets GPCR: inhibition of histone H3 methyltransferase (G9a) and histamine H(3) receptor for Prader-Willi Syndrome. Sci Rep 10, 13558.
• Herrlinger E.M., Hau M., Redhaber D.M., Greve G., Willmann D., Steimle S., Müller M., Lübbert M., Miething C.C., Schüle R. and Jung M. (2020) Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells. Chembiochem 21, 2329-2347.
• Brosowsky J., Lutterbeck M., Liebich A., Keller M., Herp D., Vogelmann A., Jung M. and Breit B. (2020) Syntheses of Thailandepsin B Pseudo-Natural Products: Access to New Highly Potent HDAC Inhibitors via Late-Stage Modification. Chemistry, doi: 10.1002/chem.202002449.
• Xiong Y., Greschik H., Johansson C., Seifert L., Bacher J., Park K.S., Babault N., Martini M., Fagan V., Li F.L., Chau I., Christott T., Dilworth D., Barsyte-Lovejoy D., Vedadi M., Arrowsmith C.H., Brennan P., Fedorov O., Jung M., Farnie G., Liu J., Oppermann U., Schule R. and Jin J. (2019) Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1). Journal of Medicinal Chemistry 62, 8996-9007.
• Roatsch M., Hoffmann I., Abboud M.I., Hancock R.L., Tarhonskaya H., Hsu K.F., Wilkins S.E., Yeh T.L., Lippl K., Serrer K., Moneke I., Ahrens T.D., Robaa D., Wenzler S., Barthes N.P.F., Franz H., Sippl W., Lassmann S., Diederichs S., Schleicher E., Schofield C.J., Kawamura A., Schule R. and Jung M. (2019) The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases. ACS Chem Biol 14, 1737-1750.
• Simon R.P., Rumpf T., Linkuviene V., Matulis D., Akhtar A. and Jung M. (2019) Cofactor Analogues as Active Site Probes in Lysine Acetyltransferases. J Med Chem 62, 2582-2597.
• 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.  
• Barth J., Abou-El-Ardat K., Dalic D., Kurrle N., Maier A.M., Mohr S., Schutte J., Vassen L., Greve G., Schulz-Fincke J., Schmitt M., Tosic M., Metzger E., Bug G., Khandanpour C., Wagner S.A., Lubbert M., Jung M., Serve H., Schule R. and Berg T. (2019) LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML. Leukemia 33, 1411-1426.
• 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. (2018) 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. (2018) Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals). J Med Chem 61, 482-491.
• 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.
• 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
• 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]
• 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.