Martin-Luther-Universität Halle-Wittenberg

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Assoc. Prof. Dr. Hany Ibrahim


Tel. ++49 345 55 24887

email: hany.s.ibrahim(at)gmail.com

Entwicklung von niedermolekularen Inhibitoren und PROTACs für histonmodifizierende Enzyme

Funded by the Alexander von Humboldt Foundation

Degradation of proteins of interest using heterobifunctional small molecules to hijack the ubiquitin-proteasome system has been recently discovered as a novel tool for biological research and for the discovery of new drug candidates. Such compounds, named PROTACs (Proteolysis Targeting Chimera), are hybrid molecules that consist of two pharmacophores, one capable of binding the protein to be degraded and a second part that is binding to the E3 ubiquitin ligase complex, connected by a linker. PROTACs recruit the protein of interest and bring them into proximity with the E3 ligase through formation of a ternary complex. This results in ubiquitination of the target protein and a subsequent degradation by the 26S proteasome.

We are interested in applying the PROTAC concept in the field of histone deacetylases (HDACs). HDACs catalyze the de-acetylation process from the N-terminal of lysine residue of histone protein as well as non-histone proteins. Deacetylation processes have numerous consequences depending on the deacetylated substrate. For example, it leads to a condensation of the chromatin structure and hence, DNA will be less accessible for translation. HDACs are considered as drug target to treat diseases where de-acetylation process is distorted, such as cancer, HIV latent infection and Alzheimer’s disease. HDACs are classified into four different classes based on their sequence similarity. In the current study we will mainly focus on HDAC class I, which includes four different isoforms (HDAC 1, 2, 3 and 8) that are located mainly in the nucleus.

The planned research activity will focus on the design of novel isoform selective HDAC inhibitors using novel chemotypes. In addition we plan to design selective PROTACs that will be used for the selective degradation of individual HDACs.

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