M. Sc. Patrik Zeyen
Tel. ++49 345 55 25188
e-mail: patrik.zeyen(at)pharmazie.uni-halle.de
Development of novel histondeacetylase 8/10 inhibitors for tumor therapy
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 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 homologues in complex with inhibitors as well as homology models of HDAC10 will be used for structure- and computer-based optimization of the 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, both in-vitro and in cell culture. Selected improved inhibitors will be subjected to animal studies to clarify the potential of HDAC8 and 10 for future drug development. The different expertise of the three groups from computational chemistry via synthesis and screening to biological and preclinical drug testing will facilitate a unique synergy to achieve the goals of this proposal.
Publications/Poster
2021
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 15(3), e0009226, 2021. 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
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