Dr. Dina Robaa
Dr. rer. nat. Dina Robaa
Tel. ++49 345 55 25045
e-mail: dina.robaa(at)pharmazie.uni-halle.de
Structure-based design and optimization of inhibitors of histone methyltransferases
Histone modifications are one of the most important epigenetic mechanisms by which the organism regulates the transcriptional process of the genetic code. Histones are highly basic proteins; their N-terminal tails can be modified by various biochemical reactions, like acetylation, methylation, phosphorylation, ubiquitination and sumoylation. Drugs which target this epigenetic process, like some histone deacetylase inhibitors, are already implemented or close at hand for clinical use in antineoplastic therapy.
Histone methyltransferases, which comprise protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs), are a class of epigenetic enzymes responsible for the methylation of lysine and arginine residues in the histone tails as well as in other non-histone targets. Several links between patterns of histone methylation and cancer progression have been established and both enzyme classes have also been correlated with other diseases including diabetes, atherosclerosis and with the pathogenesis of some viruses like HIV. To date only few inhibitors of histone methyltransferases are known.
Protein arginine methytransferase inhibitors:
PRMTs are a highly conserved family of proteins, which catalyze the N-methylation of the guanidine rest in arginine to form mono- and/or dimethylated arginines, depending on the PRMT subtype involved. Eleven subtypes of PRMTs have so far been identified; nine of them have proven to possess enzymatic activity.
Through a target-based approach several inhibitors of PRMT1 have already been identified; their inhibitory potency lied however in the micromolar range. Optimization of the obtained active scaffolds by docking studies to guide subsequent synthetic modifications is carried out to try and improve the inhibitory potency. Moreover, virtual screening of various commercial databases and pharmacophore-based approaches are adopted to identify other interesting structural scaffolds as potential PRMT1 inhibitors. Similar approaches are used to search for inhibitors of PRMT6; another type I PRMT which shows a high sequence similarity with PRMT1.
Publcations
2019
K. Vögerl, N. Ong, J. Senger, D. Herp, K. Schmidkunz, M. Marek, M. Müller M, K. Bartel, T. Shaik, N. Porter, D. Robaa, D. Christianson, C. Romier, W. Sippl, M. Jung, F Bracher. Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 (HDAC6) Inhibitors. J Med Chem. 2019 Jan 15. doi:10.1021/acs.jmedchem.8b01090 .
A. Haider, A. Müller Herde, S. D. Krämer, J. Varisco, C. Keller, K. Frauenknech, Y. P. Auberson, L. Temme, D. Robaa, W. Sippl, R. Schibli, B. Wünsch, L. Mu, S. M. Ametamey. Preclinical Evaluation of Benzazepine-Based PET Radioligands (R)- and (S)-11C-Me-NB1 Reveals Distinct Enantiomeric Binding Patterns and Tightrope Walk between GluN2B- and Sigma1 Receptor-Targeted PET Imaging. J Nucl Med. 2019 Jan 25. pii: jnumed.118.221051. doi:10.2967/jnumed.118.221051 . [Epub ahead of print]
2018
E. Plesch, C.C. Chen, E. Butz, A.S. Rosato, E. K Krogsaeter, H. Yinan, K. Bartel, M. Keller, D. Robaa, D. Teupser, L. M. Holdt, A.M. Vollmar, W. Sippl, R. Puertollano, D. Medina, M. Biel, C, Wahl-Schott, F. Bracher, C. Grimm. Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells. eLife 7, e39720, 2018. doi:10.7554/eLife.39720
M. Marek, T.B. Shaik, T. Heimburg, A. Chakrabarti, J. Lancelot, E. Ramos-Morales, C. Da Veiga, D. Kalinin, J. Melesina, D. Robaa, K. Schmidtkunz, T. Suzuki, R. Holl, E. Ennifar, R.J. Pierce, M Jung, W. Sippl, C. Romier. Dissecting the molecular basis of HDAC8 selective inhibition reveals specific active site structural and functional determinants. J Med Chem. 61, 10000-10016, 2018. doi:10.1021/acs.jmedchem.8b01087
T. Bayer, A. Chakrabarti, J. Lancelot, T. B. Shaik, K. Hausmann, J. Melesina, K. Schmidtkunz, M. Marek, F. Erdmann, M. Schmidt, D. Robaa, C. Romier, R. J. Pierce, M. Jung and W. Sippl. Synthesis, crystallization studies and in vitro characterization of novel cinnamic acid derivatives as SmHDAC8 inhibitors for the treatment of Schistosomiasis. Chem. Med. Chem., 15, 1517-1529, 2018. doi:10.1002/cmdc.201800238 .
C. Luise, D. Robaa. Application of Virtual Screening Approaches for the Identification of Small Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1. Methods Mol Biol. 1824, 347-370, 2018. doi:10.1007/978-1-4939-8630-9_21.
Hauser AT, Robaa D, Jung M. Epigenetic small molecule modulators of histone and DNA methylation. Curr Opin Chem Biol. 2018 Mar 23;45:73-85. doi:10.1016/j.cbpa.2018.03.003
M. J. Chua, D. Robaa, T. S. Skinner-Adams, W. Sippl and K. T Andrews. Activity of bromodomain protein inhibitors/binders against asexual-stage Plasmodium falciparum parasites. International Journal for Parasitology: Drugs and Drug Resistance, March 2018, doi:10.1016/j.ijpddr.2018.03.001
C. V. Simoben, D. Robaa, A. Chakrabarti, K. Schmidtkunz, M. Marek, J. Lancelot, S. Kannan, J. Melesina, T. B. Shaik, R. J. Pierce, C. Romier, M. Jung and W. Sippl. A novel class of Schistosoma mansoni histone deacetylase 8 (HDAC8) inhibitors identified by structure-based virtual screening and in vitro testing. Molecules ;23(3). pii: E566. doi:10.3390/molecules23030566
L. Temme, B. Frehland, D. Schepmann, D. Robaa, W. Sippl, B. Wünsch. Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation. Eur. J. Med. Chem. 144, 672-681, 2018. doi:10.1016/j.ejmech.2017.12.054
J. Schulz-Fincke, M. Hau, J. Barth, D. Robaa, D. Willmann, A. Kürner, J. Haas, G. Greeve, T. Haydn, S. Fulda, E. Metzger, M. Lübbert, S. Lüdeke, T. Berg, W. Sippl, R. Schüle, and M. Jung. Structure-Activity Studies on N-Substituted Tranylcypromine Derivatives Lead to Selective 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, 2018. doi.org/10.1016/j.ejmech.2017.12.001
M. Schiedel, D. Herp, S. Hammelmann, S. Swyter, A. Lehotzky, D Robaa, J. Oláh, J. Ovádi, W. Sippl, M. Jung. 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, 2018. doi:10.1021/acs.jmedchem.6b01872
M. Schiedel, D. Robaa, T. Rumpf, W. Sippl, M. Jung. The Current State of NAD+-Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets. Med. Res. Rev. 38(1), 147-200, 2018. doi:10.1002/med.21436.
2017
T. Heimburg, F. R. Kolbinger, P. Zeyen, E. Ghazy, D. Herp, K. Schmidtkunz, J. Melesina, T. B. Shaik, F. Erdmann, M. Schmidt, C. Romier, D. Robaa, O. Witt, I. Oehme, M. Jung, and W. SipplStructure-based design and biological characterization of selective HDAC8 inhibitors with anti-neuroblastoma activityJ. Med. Chem, 60, 10188-10204, 2017. DOI:10.1021/acs.jmedchem.7b01447
S. Gawaskar, L. Temme, J. A. Schreiber, D. Schepmann, A. Bonifazi, D. Robaa, W. Sippl, N. Strutz-Seebohm, G. Seebohm, B. Wünsch. Design, synthesis, pharmacological evaluation and docking studies of novel GluN2B selective NMDA receptor antagonists with benzo[7]annulen-7-amine scaffold. ChemMedChem 12(15):1212-1222, 2017. doi:10.1002/cmdc.201700311 .
D. Wutz, D. Gluhacevic, A. Chakrabarti, K. Schmidtkunz, D. Robaa, F. Erdmann, C. Romier, W. Sippl, M. Jung, B. König. Photochromic histone deacetylase inhibitors based on dithienylethenes and fulgimides. Org Biomol Chem. 15, 4882-4896, 2017. doi:10.1039/c7ob00976c.
L. L. S. Scholte, M. M. Mourãa, F. Sviatopolk-Mirsky Paisa, J. Melesina, D. Robaa, A. C. Volpini, W. Sippl, R. J. Piercee, G. Oliveira, L. A. Nahum. Evolutionary relationships among protein lysine deacetylases of parasites causing neglected diseases. Infect Genet Evol. 53:175-188, 2017 doi:10.1016/j.meegid.2017.05.011
G. S. Hailu, D. Robaa, M. Forgione, M.W. Sippl, D. Rotili, A. Mai. Potential of Histone Deacetylase Inhibitors as Anti-Parasitic Agents. J. Med. Chem. 60, 4780-4804, 2017. doi:10.1021/acs.jmedchem.6b01595 .
B. Sauer, T. S. Skinner-Adams, A. Bouchut, M. J. Chua, C. Pierrot, F. Erdmann, D. Robaa, M. Schmidt, J. Khalife, K. T. Andrews, W. SipplSynthesis, biological characterisation and structure activity relationships of aromatic bisamidines active against Plasmodium falciparum. Eur. J. Med. Chem. 127, 22-40, 2017. doi:10.1016/j.ejmech.2016.12.041.
D.Lehmann, L. Motlagh, D. Robaa, S. ZierzMuscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical FeaturesInt J Mol Sci.18(1). pii: E82, 2017. doi:10.3390/ijms18010082
2016
D. Robaa, T. Wagner, C. Luise, L. Carlino, J. McMillan, R. Flaig, R. Schüle, M. Jung, and W. Sippl. Identification and SAR studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1. ChemMedChem.11, 2327-2338, 2016. doi:10.1002/cmdc.201600362
M. Roatsch, D. Robaa, M. Pippel, J. E. Nettleship, Y. Reddivari, L. E. Bird, I. Hoffmann, H. Franz, R. J. Owens, R. Schüle, R. Flaig, W. Sippl, M. Jung. Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases. Future Med. Chem. 8, 1553-71, 2016. doi:10.4155/fmc.15.188 .
T. Heimburg, A. Chakrabarti, M. Marek, J. Lancelot, J. Melesina, D. Robaa, F. Erdmann, M. Schmidt, R. J. Pierce, C. Romier, M. Jung and W. Sippl. Structure-Based Design and Synthesis of Novel Inhibitors targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis. J. Med. Chem, 59, 2423-35, 2016. DOI:10.1021/acs.jmedchem.5b01478
R. P. Simon, D. Robaa, Z. Al Halabi, W. Sippl and M. Jung. KATching-up on Histone Acetyltransferase Inhibitors. J. Med. Chem. 59, 1249–1270, 2016. DOI:10.1021/acs.jmedchem.5b01502
Q. Y. Zhu, Zhou, C. Chen, S. Heinemann, R. El-Mergawy, R. Schönherr, D. Robaa, W. Sippl, G. Scriba. Stereospecific capillary electrophoresis assays using pentapeptide substrates for the study of Aspergillus nidulans methionine sulfoxide. Electrophoresis 37, 2083-90, 2016. doi:10.1002/elps.201600181.
T. Wagner, D. Robaa, W. Sippl, M. Jung Epigenetic Readers Interpreting the Lysine Methylome - Biological Roles and Drug Discovery.in: Drug Discovery in Cancer Epigenetics (Eds.: G. Egger, P. Arimondo) 273-304, 2016.
2015
S. Gawaskar, D. Schepmann, A. Bonifazi, D. Robaa, W. Sippl, B. Wünsch. Benzo[7]annulene-based GluN2B selective NMDA receptor antagonists: surprising effect of a nitro group in 2-position. Bioorg Med Chem Lett. 25, 5748-51, 2015. doi:10.1016/j.bmcl.2015.10.076.
B. Tewes, B. Frehland, D. Schepmann, D. Robaa, T. Uengwetwanit, F. Gaube, T. Winckler, W. Sippl, B. Wünsch. Enantiomerically pure 2-methyltetrahydro-3-benzazepin-1-ols as GluN2B-selective NMDA receptor antagonists. J Med Chem 58, 6293-305. DOI:10.1021/acs.jmedchem.5b00897
T. Uengwetwanit, D. Robaa, W. Sippl. Analysis of the Resistance of Hepatitis C virus NS5B polymerase inhibitors via Docking and Molecular Dynamics Simulation. Mol. Inf. 34, 78-83, 2015. doi:10.1002/minf.201400048
2014
S. Furdas, I. Hoffmann, D. Robaa, W. Malinka, P. Swiatek, W. Sippl, M. Jung. Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs). Med Chem Comm, 5, 1856-1862, 2014i. doi:10.1039/c4md00245h
T. Wagner, D. Robaa, W. Sippl, M. Jung. Mind the Methyl - Methyl Lysine Binding Proteins in Epigenetic Regulation. Chem Med Chem 9 (3), 466-83, 2014. doi:10.1002/cmdc.201300422
2012
K. Kölbel, C. Ihling, U. Kühn, I. Neundorf, S. Otto, J. Stichel, D. Robaa,
A. G. Beck-Sickinger, A. Sinz, E. Wahle.
Peptide backbone conformation affects the substrate preference of protein arginine methyltransferase I.
Biochemistry, 51(27), 5463-7, 2012.
M. Schulze, O. Siol, D. Robaa, F. K. Mueller, C. Enzensperger, C. Fleck,
J. Lehmann.
Molecular combination of the dopamine and serotonin scaffolds yield in novel antipsychotic drug candidates - characterization by in vivo experiments.
Arzneimittelforschung, 62(5), 252-60, 2012.
2011
D. Robaa, C. Enzensperger, S. Eldin Abulazm, M.M. Hefnawy,
H. I. El-Subbagh, T. A. Wani, J. Lehmann.
Chiral indolo[3,2-f][3]benzazecine-type dopamine receptor antagonists: synthesis and activity of racemic and enantiopure derivatives.
J. Med. Chem., 54(20), 7422-6, 2011.
D. Robaa, S. Eldin AbulAzm, J. Lehmann, C. Enzensperger.
A novel non-phenolic dibenzazecine derivative with nanomolar affinities for dopamine receptors.
Chem. Biodivers., 8(3), 431-9, 2011.
2010
D. Robaa, R. Kretschmer, O. Siol, S. Eldin Abulazm , E. Elkhawass,
J. Lehmann, C. Enzensperger.
Residues at the indole-NH of LE300 modulate affinities and selectivities for dopamine receptors.
Arch Pharm (Weinheim), 344(1), 28-36, 2010.
D. Robaa, C. Enzensperger, S. Eldin Abulazm, E. Elkhawass, O. ElSayed,
J. Lehmann.
Dopamine receptor ligands. Part 18: modification of the structural skeleton of indolobenzazecine-type dopamine receptor antagonists.
J. Med. Chem., 53(6), 2646-50, 2010.
Posters
2015
B. Sauer, D. Robaa, M. Schmidt, K. Andrews, C. Pierrot, A. Bouchut, J. Khalife, W. Sippl. Synthesis and Antiparasitic Activity of Aromatic Bisamidines. DPhG Annual Meeting 2015 23.09.- 25.09.2015, Düsseldorf
D. Robaa, B. Sauer, T. Wagner, M. Schmidt, M. Jung, W. Sippl. Computer-based studies of Bisamidines as PRMT1 and PRMT6 inhibitors. DPhG Annual Meeting 2015 23.09.- 25.09.2015, Düsseldorf
A.K.Najjar, D. Robaa, W. Sippl. Structure-based Development of Novel Inhibitors for the Epigenetic Target EZH2. Central German Meeting on Bioinformatics26-27.08. 2015, Halle, Germany.
2013
B.Sauer, D. Robaa, T. Wagner, M. Jung, M. Schmidt, W. Sippl.
Synthesis of Bisamidines as PRMT Inhibitors
DPhG Annual Meeting 2013
09.-11.10.2013, Freiburg
2012
D. Robaa, T. Wagner, M. Jung, W. Sippl
Structure-based design of PRMT6 inhibitors
19th EuroQSAR
26.-30.08.2012, Vienna