Cancer represents a group of related disorders, characterised by uncontrolled cell division. The disease develops as a result of irreparable changes in the nucleus of the cell, i.e. gene mutations in sex cells or body cells. Cancer treatment involves the use of drugs to halt cell division and cause cell apoptosis. An important development for future cancer therapeutics was the discovery of targeted protein degradation by PROTAC molecules, which take advantage of the cell’s naturally occurring mechanisms for degradation of damaged proteins. PROTAC-based cancer treatment aims to control the activity of pathologically-relevant proteins by lowering their concentrations. An advantage of using PROTACs in cancer therapy lies in the fact that PROTACs dissociate from both of their binding sites, act as a catalyst, and thereby achieve an almost total protein degradation even in substoichiometric amounts. The human genome encodes for more than 600 different E3 ligases, however, only a number of them have been successfully applied in PROTAC design. Most of the recently synthesised PROTACs target the cereblon ligase. Ligands for this E3 ligase are synthetically accessible, have high binding affinity and favourable physico-chemical properties. Cereblon is a protein composed of 442 amino acids and is the primary target of immunomodulatory imide drugs. The binding of these drugs enhances the interaction with the IKZF1 and IKZF3 transcription factors, resulting in their ubiquitination and degradation, ultimately causing an antiproliferative effect in multiple myeloma. The majority of the PROTAC molecules which act via cereblon-induced degradation consist of thalidomide, lenalidomide or pomalidomide derivatives.
In this master’s project, we have synthesised four new cereblon ligands, which are potentially useful as tools for studying the biological role of cereblon and as building blocks of PROTACs. Ligand design was based on the formation of a planar open ring, which resembles thalidomide and is composed of 4-aminobenzoic acid with different ortho-substituents, connected to the glutarimide component via an amide bond. Ligand synthesis was based on amide bond formation and subsequent reduction. In collaboration with the Charité clinical centre in Berlin, the binding affinities of the synthesised ligands for cereblon were determined. Results revealed that ligands with the hydroxy- and methoxy-substitution exhibit similar binding affinities as thalidomide, while the affinities of the chloro- and methyl-substituted ligands were slightly worse.
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