Rizwana Ayub
Rizwana Ayub
Tel. ++49 345 55 25188
e-mail: rizwana.ayub(at)pharmazie.uni-halle.de
Development of novel HDAC Inhibitors and PROTACs
Histone deacetylases (HDAC) 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 HDAC10 as well as homology models of HDAC11 will be used for structure- and computer-based optimization of novel non-hydroxamate scaffolds. Compounds will be optimized 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 yet unexplored HDAC isoforms for future drug development. Another starting point is the development of protein-degrading agents, the so-called PROTACs, for the HDACs under investigation. PROTACs are designed to specifically degrade HDACs in the cancer cells under investigation in order to better understand their biological role.