Novel Organic Proteasome Inhibitors Identified by Virtual and in Vitro Screening

Abstract

Proteasome inhibition is a promising strategy for treating cancers. Herein, we report the discovery of novel drug-like inhibitors of mammalian proteasome 20S using a multistep structure-based virtual ligand screening strategy. Sulfone- or piperazine-containing hits essentially belong to the under-represented class of noncovalent and nonpeptidic proteasome inhibitors. Several of our compounds act in the micromolar range and are cytotoxic on human tumoral cell lines. Optimization of these molecules could lead to better anticancer therapy.

Substituted quinolines as noncovalent proteasome inhibitors

“…Examples of nonpeptidic noncovalent proteasome modulators include the phakellins, 25 oxadiazoles, 26 hydroxyureas, 24 imidazolines 27,28 sulfone or piperazine agents, 29 and tamoxifen derivatives. 30 …”

Inhibitors of Proteinases as Potential Anti-Cancer Agents

“…Twenty of these molecules appeared to act as potent proteasome inhibitors showing variable profiles of activity. Thus six of them inhibited all three activities of proteasome, eleven of them inhibited two types of enzymatic activities, whereas three inhibited only one type of activity (Basse et al, 2010). The most active and selective inhibitors against chymotrypsin-like and trypsin-like activities are shown in Figure 20.…”

Blockade of the malignant phenotype by β-subunit selective noncovalent inhibition of immuno- and constitutive proteasomes

“…Some molecules contain a N -capped dipeptide backbone (compounds A1a-b, Figure 1B) [10, 11] or mimic the natural cyclic tripeptide TMC-95 (compound A2) [12–14] (Figure 1B). Recently reported noncovalent inhibitors are now essentially organic compounds [15–21] (compounds A3-A7, Figure 1B). Since noncovalent inhibitors are in general devoid of reactive groups, they do not have the drawbacks generally associated with the presence of a warhead such as lack of specificity, instability, and excessive reactivity [9].…”