Dr. Ehab Ghazy
Dr. Ehab Ghazy, MSc.
e-mail:ehab.ghazy(at)pharmazie.uni-halle.de
Chemical optimization of HDAC inhibitors
Histone deacetylases are important modulators of epigenetic gene regulation and the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. In the current work, by combining computer-based approaches, organic synthesis and in vitro testing, selective inhibitors for HDAC8 shall be developed. Crystal structures of HDAC8 and homologues in complex with inhibitors will be used for structure- and computer-based optimization of inhibitors. Based on docking studies and computational analysis of the conformational flexibility of HDAC8 and HDAC10 by means of molecular dynamics simulationhs a rationale for chemical optimization of inhibitors will be deduced. Alltogether, the role of HDAC8 in the proliferation of cancer cells shall be further investigated and developed lead structures shall be optimized in a bioguided fashion for potency and selectivity.
Publications
2023
S. Hagemann, D. Misiak, J. L. Bell, T. Fuchs, M. I. Lederer, N. Bley, M. Hämmerle, E. Ghazy, W. Sippl, J. H. Schulte, S. Hüttelmaier. IGF2BP1 induces high-risk neuroblastoma and forms a druggable feedforward loop with MYCN promoting 17q oncogene expression. Mol Cancer. 22(1):88, 2023. doi:10.1186/s12943-023-01792-0 .
2022
S. Darwish, E. Ghazy, T. Heimburg, D. Herp, P. Zeyen, R. Salem-Alintas, J. Ridinger, D. Robaa, K. Schmidtkunz, F. Erdmann, M. Schmidt, C. Romier, M. Jung, I. Oehme, W. Sippl. Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimera (PROTAC) with Anti-Neuroblastoma Activity. Int. J. Mol. Sci. 2022, 23(14), 7535; https://doi.org/10.3390/ijms23147535
E. Ghazy, M. Abdelsalam, D. Robaa, R.J. Pierce, W. Sippl. Histone deacetylase (HDAC) inhibitors for the treatment of Schistosomiasis. Pharmaceuticals 15(1), 80, 2022. https://doi.org/10.3390/ph15010080
2021
E. Ghazy, T. Heimburg, J. Lancelot, P. Zeyen, K. Schmidtkunz, A. Truhn, S. Darwish, C. V. Simoben, M. Marek, F. Erdmann, M. Schmidt, D. Robaa, C. Romier, M. Jung, R. Pierce, W. Sippl. Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of Schistosomiasis. Eur J Med Chem. 225, 113745, 2021. doi:10.1016/j.ejmech.2021.113745
C. V. Simoben, E. Ghazy, P. Zeyen, S. Darwish, M. Schmidt, C. Romier, D. Robaa, W. Sippl. Binding free energy (BFE) calculations and quantitative struc-ture-activity relationship (QSAR) analysis of Schistosoma mansoni histone deacetylase 8 (smHDAC8) inhibitors. Molecules 26, 2584, 2021. doi.org/10.3390/molecules26092584
HR. Vaca, AM. Celentano, A. Toscanini, T. Heimburg, E. Ghazy, P. Zeyen, A. Hauser, G. Oliveira, MC. Elissondo, M. Jung, W. Sippl, F. Camicia, MC. Rosenzvit. The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. PLOS Neglected Tropical Diseases, 2021 Mar 3;15(3):e0009226. doi:10.1371/journal.pntd.0009226
2020
E. Ghazy, P. Zeyen, D. Herp, K. Schmidtkunz, M. Hügle, F. Erdmann, D. Robaa, M. Schmidt, C. Romier, S. Günther, M. Jung, W. Sippl. Design, synthesis, and biological evaluation of novel hydroxamates as dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1. Eur. J. Med. Chem. 200, 112338, 2020. doi:10.1016/j.ejmech.2020.112338
C. Glas, J. Dietschreit, N. Wössner, L. Urban, E. Ghazy, W. Sippl, M. Jung, C. Ochsenfeld, F. Bracher. Identification of the subtype-selective Sirt5 inhibitor balsalazide through systematic SAR analysis and rationalization via theoretical investigations. Eur J Med Chem. 206, 112676, 2020. doi.org/10.1016/j.ejmech.2020.112676
L. Ângelo de Souza, M. Silva E Bastos, J. de Melo Agripino, T. Souza Onofre , LF. Apaza Calla, T. Heimburg, E. Ghazy, T. Bayer, VH. Ferraz da Silva, P. Dutra Ribeiro, L. Licursi de Oliveira, G. Costa Bressan, MR. de Almeida Lamêgo, A. Silva-Júnior , R. de Souza Vasconcellos, AM. Suarez-Fontes, J. Almeida-Silva, MA. Vannier-Santos, R. Pierce, W. Sippl, J. Lopes Rangel Fietto. Histone deacetylases inhibitors as new potential drugs against Leishmania braziliensis, the main causative agent of New World Tegumentary Leishmaniasis. Biochem Pharmacol, 2020 Aug 7;180:114191. doi:10.1016/j.bcp.2020.114191
2019
M. Zessin, Z. Kutil, M. Meleshin, Z. Nováková, E. Ghazy, D. Kalbas, M. Marek, C. Romier, W. Sippl, C. Bařinka, M. Schutkowski. One-Atom-Substitution Enables Direct and Continuous Monitoring of Histone Deacylase Activity. Biochemistry. 58(48):4777-4789, 2019. doi:10.1021/acs.biochem.9b00786
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. Sippl. Structure-based design and biological characterization of selective HDAC8 inhibitors with anti-neuroblastoma activity. J. Med. Chem 60, 10188-10204, 2017. DOI:10.1021/acs.jmedchem.7b01447
Full publication list
Posters
2017
E. Ghazy, K. Schmidtkunz, D. Robaa, M. Schmidt, J. Khalife, M. M. Mourão, M. Jung, W. Sippl. Structure-based design and synthesis of novel hydroxamates as dual histone deacetylases/ bromodomains epigenetic inhibitors
13th German Peptide Symposium22.03.2017, Erlangen
2016
E. Ghazy, K. Schmidtkunz, D. Robaa, M. Schmidt, M. Jung, W. Sippl. Structure-Based Design and Synthesis of Dual Epigenetic Inhibitors of Histone Deacetylases and Bromodomains
Drug Innovation in Academia08.12 2016, Heidelberg
