Peptide and Peptide-Like Modulators of 20S Proteasome Enzymatic Activity in Cancer Cells

Abstract

The involvement of the ubiquitin-proteasome pathway in the degradation of critical intracellular regulatory proteins suggested a few years ago the potential use of proteasome inhibitors as novel therapeutic agents being applicable in many different disease indications, and in particular for cancer therapy. This article reviews recent salient medicinal chemistry achievements in the design, synthesis, and biological characterization of both synthetic and natural peptide-like proteasome inhibitors, updating recent reviews on this class of agents. As shown herein, different compound classes are capable of modulating the subunit-specific proteolytic activities of the 20S proteasome in ways not previously possible, and one of them, bortezomib, has provided proof-of-concept for this therapeutic approach in cancer clinical settings.

Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S β5-subunit

“…More recently, the β-lactone salinosporamide A (NPI-0052) [ 27 ] and the epoxyketone carfilzomib (PR-171) ( Figure 1 A) [ 28 ], which are analogues of lactacystin and epoxomicin respectively, have demonstrated activity in preclinical models of multiple myeloma and chronic lymphocytic leukaemia, and have entered clinical trials for advanced solid and haematological malignancies [ 23 ]. These covalent inhibitors have comparable potency to bortezomib, but differ in that they form essentially irreversible adducts with the active site Thr 1Oγ residues of the proteasome [ 4 , 5 , 9 , 10 , 15 , 27 – 30 ].…”

“…Although the reactive ‘warheads’ of covalent proteasome inhibitors can contribute to enzyme potency, they can also lack specificity and be excessively reactive and unstable [ 10 , 11 , 15 ], properties which may limit their efficacy in vivo . Non-covalent inhibitors that are readily reversible in their interactions with the catalytic 20S β-subunits provide an alternative mechanism for proteasome inhibition.…”

“…Such inhibitors may offer therapeutic advantages by enabling more widespread tissue distribution through their more rapid binding and dissociation kinetics. TMC-95A is a complex natural cyclic tri-peptide ( Figure 1 B) that competitively and non-covalently inhibits the chymotrypsin-like activity of the proteasome with nanomolar potency, and also inhibits the caspase-like and trypsin-like activities at higher concentrations [ 4 , 5 , 9 , 10 , 31 ]. The high affinity of TMC-95A is due to its rigid heterocyclic ring system, which provides specific hydrogen-bonding interactions within each 20S active site without covalent modification of the catalytic threonine residues [ 4 , 5 , 9 , 32 ].…”

Linear TMC-95-Based Proteasome Inhibitors

“…Most proteasome inhibitors are short peptides bearing a reactive group such as aldehyde (MG132, calpain I inhibitor Ac-Leu-Leu-Nle-H, tyropeptin A, Figure 1), boronic acid (bortezomib, Figure 1), or vinyl sulfone that forms a covalent bond with the catalytic O γ -Thr1 in the three catalytic sites. 5,6 Some natural molecules (epoxomycin, lactacystin, homobelactosin, salinosporamide) and their synthetic derivatives (omuralide) also form covalent adducts. 7 Noncovalent inhibitors have been investigated less extensively, although they should have weaker side effects in therapeutic applications.…”

“…One is responsible for chymotrypsin-like activity (CT-L, attributed to β5), the second for trypsin-like activity (T-L, β2), and the third for post-glutamyl peptide hydrolysis or post-acid activity (PGPH or PA, β1). Most proteasome inhibitors are short peptides bearing a reactive group such as aldehyde (MG132, calpain I inhibitor Ac-Leu-Leu-Nle-H, tyropeptin A, Figure ), boronic acid (bortezomib, Figure ), or vinyl sulfone that forms a covalent bond with the catalytic O γ -Thr1 in the three catalytic sites. , Some natural molecules (epoxomycin, lactacystin, homobelactosin, salinosporamide) and their synthetic derivatives (omuralide) also form covalent adducts 1 Some proteasome inhibitors.…”