Structure based development and biological characterization of selective inhibitors of histone deacetylases (HDACs) 8 and 10.

• Applicants: Professor Dr. Manfred Jung; Privatdozentin Dr. Ina Oehme; Professor Dr. Wolfgang Sippl; Professor Dr. Olaf Witt
• Subject Area: Pharmacy
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260315923

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. Optimized 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 to biological and preclinical drug testing will facilitate a unique synergy to achieve the goals of this proposal.

• DFG Programme: Research Grants