Proteasome Inhibitors: Recent Advances and New Perspectives In Medicinal Chemistry

Abstract

The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side-effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases.

Proteasome Inhibitors Affect Appressorium Formation and Pathogenicity of the Rice Blast Fungus, Magnaporthe oryzae

“…MG-132, proteasome inhibitor I (PI) and proteasome inhibitor II (PII) have been shown to be effective proteasome inhibitors in both fungi and mammals (Genin et al, 2010;Nandi et al, 2006). The proteasome inhibition activity during M. oryzae germination and appressorium formation was first confirmed.…”

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

“…Covalent inhibitors are mainly electrophilic and react with the catalytic γ-hydroxyl of Thr1 in the active sites. In result, they either reversibly (majority of peptide aldehydes, peptide boronates, polyphenols and terpenoids) or irreversibly (majority of epoxyketones, peptide vinyl derivatives, b-Lactones and derivatives) inhibit the proteasome [19][20][21]. It should be emphasized that many of well-known natural proteasome inhibitors, such as epoxomicin, lactacystin and syringolin A belong to covalent inhibitors.…”

“…The lack of reactive group in non-covalent inhibitors is often associated with poor specificity and instability [22]. Their interaction with the proteasome active sites occurs via weak bonds (hydrophobic, electrostatic, hydrogen and/or van der Waals) [19]. The actions of proteasome inhibitors are multidirectional including control of cell cycle, regulation of pro-and anti-apoptotic proteins, sensitization to ligand-induced apoptosis, activation of bone morphogenetic protein signalling, and global translational repression (for review see [21]).…”

Studies of C-terminal naphthoquinone dipeptides as 20S proteasome inhibitors

“…As the essential role of the proteasome in cell function, inhibitors of this multicatalytic complex are potential drugs suitable in various therapeutic applications. Many natural and synthetic molecules have been studied as 20S catalytic subunits inhibitors [10][11][12][13][14][15][16][17][18][19] , among those the boronic pseudodipeptide bortezomib was the first FDA approved proteasome inhibitor for the treatment of multiple myeloma (MM) and recently carfilzomib became the second FDA-approved to treat MM in advanced state 20,21 .…”