Identification of a potent and rapidly reversible inhibitor of the 20S-proteasome

Purandare, Ashok V.; Wan, Honghe; Laing, Naomi; Benbatoul, Khalid; Vaccaro, Wayne; Poss, Michael A.

doi:10.1016/j.bmcl.2004.06.084

Cited by 18 publications

(8 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In regard to boronates as PIs, only a couple of attempts have been done till now. From a focused screening carried out at the Bristol‐Myers Squibb, the lactam‐based boronate 23 emerged as potent and β5‐selective PI . This compound was subsequently optimized according to the scheme depicted in Figure .…”

Section: Peptide Boronatesmentioning

confidence: 99%

See 1 more Smart Citation

Peptide‐Based Proteasome Inhibitors in Anticancer Drug Design

Micale

Scarbaci

Troiano

et al. 2014

Medicinal Research Reviews

View full text Add to dashboard Cite

The identification of the key role of the eukaryotic 26S proteasome in regulated intracellular proteolysis and its importance as a target in many pathological conditions wherein the proteasomal activity is defective (e.g., malignancies, autoimmune diseases, neurodegenerative diseases, etc.) prompted several research groups to the development of specific inhibitors of this multicatalytic complex with the aim of obtaining valid drug candidates. In regard to the anticancer therapy, the peptide boronate bortezomib (Velcade®) represents the first molecule approved by FDA for the treatment of multiple myeloma in 2003 and mantle cell lymphoma in 2006. Since then, a plethora of molecules targeting the proteasome have been identified as potential anticancer agents and a few of them reached clinical trials or are already in the market (i.e., carfilzomib; Kyprolis®). In most cases, the design of new proteasome inhibitors (PIs) takes into account a proven peptide or pseudopeptide motif as a base structure and places other chemical entities throughout the peptide skeleton in such a way to create an efficacious network of interactions within the catalytic sites. The purpose of this review is to provide an in-depth look at the current state of the research in the field of peptide-based PIs, specifically those ones that might find an application as anticancer agents.

show abstract

Section: Peptide Boronatesmentioning

confidence: 99%

“…The most interesting insights of this class of derivatives are the stereochemistry at Cα of the lactam ring [( R )‐isomer 12‐fold more active than ( S )‐isomer] and the side chain at P 1 that also influences the reversible nature of the inhibition (Et → rapidly reversible vs. i Bu → slowly reversible) …”

Section: Peptide Boronatesmentioning

confidence: 99%

Peptide‐Based Proteasome Inhibitors in Anticancer Drug Design

Micale

Scarbaci

Troiano

et al. 2014

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…In addition, proteasome inhibitors could be used as therapeutic agents to arrest tumor cell proliferation and as modulators of antigen presentation. The most common inhibitors are peptide-based compounds with a C-terminal function, able to interact with enzymatic catalytic threonine. − …”

Section: Introductionmentioning

confidence: 99%

“…The most common inhibitors are peptide-based compounds with a C-terminal function, able to interact with enzymatic catalytic threonine. [9][10][11][12][13][14][15][16][17][18] We recently reported the identification of some tripeptidic sequences functionalized with arecoline deriva-tives. 19,20 The more effective of these molecules, which carry an N-terminal 1,2,5,6-tetrahydropyridine-3-carbonyl (Guv, guvacine) group, have shown an interesting inhibition of the tryptic-and chymotryptic-like activities of the proteasome and favorable pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

Peptidyl Vinyl Ester Derivatives: New Class of Selective Inhibitors of Proteasome Trypsin-Like Activity

et al. 2005

View full text Add to dashboard Cite

The proteasome is a multicatalytic proteinase complex which plays a central role in intracellular protein degradation. We report here the synthesis and biological activities of a new class of specific proteasome inhibitors selective for trypsin-like activity. These tripeptide-based compounds bearing a C-terminal vinyl ester are nontoxic, and do not affect cell proliferation, but are able to modulate the generation and presentation of immunogenic peptides presented by MHC class I molecules.

show abstract

“…While many of the newly discovered or synthesized proteasome inhibitors have not been fully characterized they can provisionally be classified as competitive based solely on their known chemical structure. This is the case of a new lactam boronic acid derivative [128] and boronic acid peptidomimetics: retro hydrazine-azapeptoids [129], with a mechanism of binding presumably similar to other boronic acid inhibitors [130]. Peptidyl vinyl esters derivatives [131] and arecoline tripeptides [132] have been designed to competitively react with the active site threonines.…”

Section: Novel Inhibitors Of the Proteasomementioning

confidence: 98%

Allosteric Regulators of the Proteasome: Potential Drugs and a Novel Approach for Drug Design

Tan¹,

Osmulski²,

Gaczyńska³

2006

CMC

View full text Add to dashboard Cite

The proteasome recently gained an exceptional attention as a novel drug target, therefore its inhibitors became important subjects for rational drug design. A synthetic competitive inhibitor Velcade was lately approved in a fast-track process to treat multiple myeloma and is tested with other types of cancers. The proteasome is a major proteolytic assembly in eukaryotic cells responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and apoptosis. The ubiquitin-proteasome pathway has been implicated in many diseases such as cancer, autoimmune diseases, inflammation, and stroke. The activity of the proteasome can be blocked for therapeutic purposes with competitive inhibitors like Velcade, which trigger apoptosis in target cells. However, much more versatile outcomes and a true control of the proteasome can be achieved with allosteric regulators. Certain natural proteins and peptides bind to the catalytic core of the proteasome and allosterically induce a wide array of effects ranging from changes in product size to substrate-specific inhibition. Designing small synthetic compounds allosterically interacting with the proteasome represents a novel approach that has enormous potential for the treatment of a wide range of diseases. Below we provide a review of current knowledge about proteasomal allosteric ligands.

show abstract

Identification of a potent and rapidly reversible inhibitor of the 20S-proteasome

Cited by 18 publications

References 9 publications

Peptide‐Based Proteasome Inhibitors in Anticancer Drug Design

Peptide‐Based Proteasome Inhibitors in Anticancer Drug Design

Peptidyl Vinyl Ester Derivatives: New Class of Selective Inhibitors of Proteasome Trypsin-Like Activity

Allosteric Regulators of the Proteasome: Potential Drugs and a Novel Approach for Drug Design

Contact Info

Product

Resources

About