Proteasome inhibitors for cancer therapy

The proteasome and its biological relevance

Proteasomes are 2.5 MDa holoenzyme complexes located in the nucleus and cytoplasm of eukaryotic cells (1). They are responsible for the degradation of unneeded or damaged proteins in cells, controlling key cellular processes such as the cell cycle, signal transduction, transcription, stress signalling, cell differentiation and apoptosis to name only a few (2). Proteolysis (hydrolysis of peptide bonds) is mediated by the ubiquitin-proteasome system, which modifies the proteins with multiple ubiquitin units and tags them for further destruction. During the degradation process, the hydroxy group of a N-terminal threonine unit in the active site gets deprotonated and subsequently facilitates the nucleophilic cleavage of peptide bonds. (Figure 1).
Proteasome catalytic mechanism

Figure 1: Catalytic mechanism of proteasomes (3)

The proteasome as a target for anticancer drugs

It appears that an elevated proteasome activity is present in tumour cells, condition that reflects their need to eliminate many immature and irregular proteins that would be otherwise harmful to the cell. Consequently, proteasome is an important therapeutic target and its inhibition results in a valuable and powerful tool in the treatment of certain types of cancer (4). Due to the higher levels of proteasome activity in tumour cells compared with the healthy ones, they are more sensitive to the inhibition and to subsequent apoptosis (5).

Small-molecule inhibitors targeting the proteasome's degrading activity have been extensively developed as lead compounds for various human diseases. They have proven to be clinically applicable with significant therapeutic benefits and minimal safety issues, especially to the late-stages of cancer patients.

Examples of proteasome inhibitors with therapeutic benefits

There are a wide variety of compounds that have been used, or are still under study, for their activity as proteasome inhibitors. Most of them bear electrophilic groups that covalently attach to the proteasome through nucleophilic attack of the threonine hydroxy groups (6).

The proteasome inhibitors can be classified into synthetic compounds and natural products. Regarding the synthetic ones, the majority of them are peptide-based molecules with competitive inhibition modes, such as bortezomib. After its approval by the FDA in 2003 for the treatment of multiple myeloma, the use of bortezomib has increased the survival rate of patients from 10% to 40-50%. Bortezomib served as starting point for the development of new proteasome inhibitors to the clinic. Some natural products are also able to inhibit proteasome selectively without side effects. Some examples are salinosporamides A (currently in Phase I of clinical trials) and B, omuralide and oxazolomycin A (Figure 2), small molecules with β-lactone-γ-lactame structures. They irreversibly bind to several subunits of the proteasome, having excellent specificity and IC50 values in the nM ranges.
Proteasome inhibitors

Figure 2: Examples of synthetic and natural proteasome inhibitors

β-lactones and related targets (OxIOSCR project)

Synthetic and medicinal chemists are currently working towards the synthesis of novel specific anticancer compounds by exploring a variety of functional groups such as peptide aldehydes, boronic acids, epoxyketones, cyclic peptides, β-lactones, vinyl sulfones, macrolactones and cyclic amides (7).

In this project we will focus on β-lactones, preparing mimics and analogues of known compounds and applying them to the treatment against cancer and therefore generating new optimised drugs. We will apply a novel approach for their synthesis, using sustainable techniques such as electrochemistry, flow chemistry and biocatalysis.


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2 Goldberg, Alfred L. Biochem. Soc. Trans. 2007, 35, 12-17
3 Kisselev, Alexei F.; van der Linden, Wouter A.; Overkleeft, Herman S. Chem. Biol. 2012, 19, 99-115
4 Gulder, Tobias A. M.; Moore, Bradley S. Angew. Chem. Int. Ed. 2010, 49, 9346-9367
5 Arlt, A. et al. Oncogene. 2009, 28, 3983-3996
6 Moore, Bradley S.; Eustáquio, Alessandra S.; McGlinchey, Ryan P. Curr. Opin. Chem. Biol. 2008, 12, 434-440
7 Rentsch, Andreas et al. Angew. Chem. Int. Ed. 2013, 52, 5450-5488