Synthesis and Pharmacology of Proteasome Inhibitors

Rentsch, Andreas; Landsberg, Dirk; Brodmann, Tobias; Bülow, Leila; Girbig, Anna-Katharina; Kalesse, Markus

doi:10.1002/anie.201207900

Cited by 84 publications

(40 citation statements)

References 283 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[6b, 9] Numerous classes of proteasome inhibitors have been described [7, 9–10] including peptide aldehydes, peptidyl boronates, epoxyketones, vinyl sulfones [11] , β-lactones [12] , hydroxyureas, [13] α-keto-aldehydes [14] and others. Many include an electrophile that targets the key nucleophilic Thr 1 residues in the catalytic β1, β3 and β5 subunits of the proteasome.…”

Section: Small Molecule-mediated Protein Stabilization: Inhibitorsmentioning

confidence: 99%

Small‐Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System

2014

View full text Add to dashboard Cite

Traditionally, biological probes and drugs have targeted the activities of proteins (such as enzymes and receptors) that can be easily controlled by small molecules. The remaining majority of the proteome has been deemed “undruggable”. By using small molecule modulators of the ubiquitin proteasome, protein levels, rather than protein activities can be targeted instead, increasing the number of druggable targets. While targeting the proteasome itself can lead to a global increase in protein levels, targeting other components of the UPS (e.g., the hundreds of E3 ubiquitin ligases) can lead to an increase in protein levels in a more targeted fashion. Alternatively, multiple strategies for inducing protein degradation with small molecule probes are emerging. With the ability to induce and inhibit the degradation of targeted proteins, small molecule modulators of the UPS have the potential to significantly expand the druggable portion of the proteome beyond traditional targets such as enzymes and receptors.

show abstract

Section: Small Molecule-mediated Protein Stabilization: Inhibitorsmentioning

confidence: 99%

Small‐Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System

2014

View full text Add to dashboard Cite

show abstract

“…1–4 By retaining the aldehyde warhead and varying the peptide backbone residues, chemists have designed and synthesized numerous peptide aldehydes and their boronate analogues that inhibit a spectrum of proteases with varying potencies. 5,6 Despite this obvious biological and clinical importance, there has not been a biosynthetic pathway elucidated for a peptide aldehyde.…”

Section: Introductionmentioning

confidence: 99%

Proteomics Guided Discovery of Flavopeptins: Anti-proliferative Aldehydes Synthesized by a Reductase Domain-Containing Non-ribosomal Peptide Synthetase

et al. 2013

View full text Add to dashboard Cite

Due to the importance of proteases in regulating cellular processes, the development of protease inhibitors has garnered great attention. Peptide-based aldehydes are a class of compounds that exhibit inhibitory activities against various proteases and proteasomes in the context of anti-proliferative treatments for cancer and other diseases. More than a dozen peptide-based natural products containing aldehydes have been discovered such as chymostatin, leupeptin, and fellutamide; however, the biosynthetic origin of the aldehyde functionality has yet to be elucidated. Herein we describe the discovery of a new group of lipopeptide aldehydes, the flavopeptins, and the corresponding biosynthetic pathway arising from an orphan gene cluster in Streptomyces sp. NRRL-F6652, a close relative of Streptomyces flavogriseus ATCC 33331. This research was initiated using a proteomics approach that screens for expressed enzymes involved in secondary metabolism in microorganisms. Flavopeptins are synthesized through a nonribosomal peptide synthetase containing a terminal NAD(P)H dependent reductase domain likely for the reductive release of the peptide with a C-terminal aldehyde. Solid phase peptide synthesis of several flavopeptin species and derivatives enabled structural verification and subsequent screening of biological activity. Flavopeptins exhibited submicromolar inhibition activities against cysteine proteases such as papain and calpain as well as the human 20S proteasome. They also showed anti-proliferative activities against multiple myeloma and lymphoma cell lines.

show abstract

“…Examples of hypoxia mimetic agents include Fe 2+ substitutes (Co 2+ , Ni 2+ )18; 2-oxoglutarate mimics such as dimethyloxalylglycine, N -oxalylglycine and N -oxalyl-D-phenylalanine1920; Fe 2+ chelators (deferoxamine also known as desferrioxamine, and AKB-4924)1821; inhibitors of PHD enzymes, for example, IOX2 (ref. 22) and the phase 3 clinical trial compound roxadustat (FG-4592)23; inhibitors of cullin neddylation (MLN4924)2425; and proteasome inhibitors26. Although widely used in biochemical and biomedical research, these reagents have poor target selectivity and affect multiple pathways, severely limiting their scope as chemical probes of hypoxic signalling.…”

mentioning

confidence: 99%

Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

et al. 2016

View full text Add to dashboard Cite

Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein–protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

show abstract

Synthesis and Pharmacology of Proteasome Inhibitors

Cited by 84 publications

References 283 publications

Small‐Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System

Small‐Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System

Proteomics Guided Discovery of Flavopeptins: Anti-proliferative Aldehydes Synthesized by a Reductase Domain-Containing Non-ribosomal Peptide Synthetase

Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

Contact Info

Product

Resources

About