Martin Luther University Halle-Wittenberg

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Lucas Praetorius

Lucas Praetorius

Lucas Praetorius

Lucas Praetorius

Apotheker Lucas Praetorius

Tel. ++49 345 5525194
e-mail: lucas.praetorius(at)

Structure- and computer-based design and optimization of HDAC8 and 10 inhibitors and investigation of Histone Deacetylase (HDAC) flexibility

Changes in epigenetic modifications play a significant role in tumor development. Histone deacetylase inhibitors (HDACi) are a class of compounds that increase acetylation of lysine residues on histone proteins by inhibiting the activity of HDAC enzymes. The inhibition of histone deacetylation is loosing the interaction between histones and DNA and thus upregulates transcription of proapoptotic genes that are aberrantly silenced in cancer cells. All in all HDACi have proven to induce apoptosis, cell cycle arrest and tumor cell differentiation in cancers and therefore are being developed for a wide range of cancer types. In addition to this, they have shown promises for the treatment of neurodegenerative diseases and immune disorders in vitro and in vivo.

Non-selective inhibitors dominate the pipeline of HDACi and only a few have been reported and are approved for the treatment of cancer. It is debated whether more selective HDAC inhibitors could limit the toxicity of HDAC inhibitor drugs and expand the therapeutic area. 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 previous work, we have identified HDACs 8 and 10 as promising anticancer targets and respective inhibitors as candidates for further optimization. Crystal structures of HDAC8 and HDAC10 will be used for structure- and computer-based optimization of developed lead structures. Within this project we will further investigate the role of HDAC8 and 10 in the proliferation of cancer cells and optimize available lead structures in a bioguided fashion for potency and selectivity. To design tailored molecules we will apply different computer-based approaches such as docking and binding free energy calculations. With the aid of these methods not only selective inhibitors should be derived but also a better understanding of HDAC flexibility should be gained.



M. Zessin, M. Meleshin, L.     Praetorius, W. Sippl, C. Barinka, M. Schutkowski, Uncovering       robust delactoylase and depyruvoylase activities of HDAC isoforms.     ACS Chem. Biol., 2022. 17(6): 1364-1375.   


J. Melesina, C. V. Simoben, L. Praetorius, E. F. Bülbül, D. Robaa,     W. Sippl, Strategies to Design Selective Histone Deacetylase       Inhibitors. ChemMedChem, 2021. 16(9): 1336-1359.   


L. Praetorius, T. Heimburg, D. Robaa, M. Zessin, M. Schutkowski, W.     Sippl, Structure- and Computer-Based Design of Inhibitors of the       Histone Fatty-Acid Deacylase HDAC11. 12th European Workshop in     Drug Design 2019, Siena (Italy)


J. Melesina, L. Praetorius, C. V. Simoben, D. Robaa, W. Sippl, Design       of selective histone deacetylase inhibitors: rethinking classical       pharmacophore. Future Med. Chem., 2018. 10(13): 1537-1540.   

L. Praetorius, E. Ghazy, M. Zessin, D. Robaa, M. Schutkowski, W.     Sippl, Computer-aided Design of Small Molecules Targeting       Histone Deacetylase 11. 14th German Conference on     Chemoinformatics 2018, German Chemical Society, Mainz     (Germany)

L. Praetorius, T. Heimburg, D. Robaa, M. Zessin, M. Schutkowski, W.     Sippl, Application of Virtual Screening, Homology Modeling, and       Molecular Dynamics Simulations to Design Isoform Selective HDAC11       Inhibitors. Annual Meeting of the German         Pharmaceutical Society 2018, Hamburg (Germany)

L. Praetorius, T. Heimburg, P. Zeyen, D. Herp, D. Robaa, M. Jung, W.     Sippl, Structure-guided Screening and Optimization to Design       Isoform Selective HDAC Inhibitors. Frontiers in Medicinal     Chemistry 2018, German Chemical Society, Jena     (Germany)


M. Wünsch, J. Senger, P. Schultheisz, S. Schwarzbich, K.     Schmidtkunz, C. Michalek, M. Klaß, S. Goskowitz, P. Borchert, L.     Praetorius, W. Sippl, M. Jung, N. Sewald, Structure–Activity       Relationship of Propargylamine-Based HDAC Inhibitors.     ChemMedChem, 2017. 12(24): 2044-2053.