Entry into a New Class of Potent Proteasome Inhibitors Having High Antiproliferative Activity by Structure-Based Design

Furet, Pascal; Imbach, Patricia; Noorani, Maria; Koeppler, Juergen; Laumen, Kurt; Lang, Marc; Guagnano, Vito; Fuerst, Peter G.; Roesel, Johannes; Zimmermann, Johann; García‐Echeverría, Carlos

doi:10.1021/jm049660v

Cited by 55 publications

(46 citation statements)

References 28 publications

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“…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].…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

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

Wójcik

2014

Folia Histochem Cytobiol.

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Abstract:The Ubiquitin-Proteasomes System (UPS) and autophagy, two main intracellular protein degradation pathways within the eukaryotic cells which were originally regarded as rather independent, seem to be very closely related. Proteasome inhibitors, including the multipathway inhibitor bortezomib, are drawing increased attention for their therapeutic potential in the treatment of chronic inflammation and cancer, especially tumours with a high degree of malignancy. The over-activation of autophagy induces cell death and may act as a powerful tumour-suppressing mechanism. However, autophagy, serving as an important mechanism to generate nutrients in time of cellular stresses, may directly contribute to the survival of cells treated with proteasome inhibitors, and in consequence, may decrease the effectiveness of therapy. Results of studies performed on several cancer cell lines demonstrated synergy between proteasome inhibitors and autophagy inhibitors. Those results became the base for ongoing clinical trials investigating autophagy inhibition in combination with anti-cancer therapies, including bortezomib. This review provides summary of the latest data on the functioning of the UPS and the mechanisms of autophagy. The new insights describing the main pathways of autophagy activation in response to UPS inhibition related to: (i) Unfolded Protein Response, (ii) PI3K/Akt/mTOR pathway, and (iii) formation of aggresomes, are discussed. It is concluded that concomitant inhibition of the two main cellular protein degradation systems may provide new therapeutic modalities for cancer treatment.

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Section: Proteasome Inhibitorsmentioning

confidence: 99%

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

Wójcik

2014

Folia Histochem Cytobiol.

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“…Many of these proteasome inhibitors are isolated from microbial (Feling et al 2003;Koguchi et al 2000) or plant (Arbiser et al 2005) sources or chemically synthesized (Furet et al 2004). Following the isolation and partial structural characterization, it is crucial that functional validation as a prototypical inhibitor be assessed.…”

Section: Discussionmentioning

confidence: 99%

Semi-high throughput method of measuring proteasome inhibition in vitro and in cultured cells

2010

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The ubiquitin proteasome-proteolytic pathway has emerged as one of the most significant pathways in modulating protein homeostasis under both normal and disease states. The use of proteasome inhibitors (PI) has played a pivotal role in understanding protein turn over. The main objective of this work was to develop a comprehensive, fast, and reliable, yet simple in vitro assay that would allow for the identification and characterization of a wide range of PIs. The assays consist of a 96-well plate high throughput (HTP) method to assess proteasome activity in Hs578T breast cancer cell extracts, purified 20S proteasome, using a fluorogenic substrate, Suc-leu-leu-val-tyr-7-AMC, specific to the chymotrypsin-like enzymatic activity of the proteasome. We showed that the chymotrypsin-like activity of the proteasome was inhibited in the two in vitro systems, albeit to different degrees. The assay system also includes two cell-based assays consisting of a vector expressing a fusion protein of green fluorescent protein (gfp) and Mouse Ornithine Decarboxylase (MODC) in Zs578T (parental Hs578T carrying the vector that expresses the fusion protein). In the cell-based assay analyses (qualitatively by microscopy and quantitatively by flow cytometry), treatment of Zs578T with PIs prevented the degradation of MODC, accumulated gfp, indicative of increased proteasome inhibition. Because no single assay represents a definitive proof of proteasome inhibitory activity, combined, these assays should serve as a comprehensive benchmark for the identification and partial characterization of novel inhibitors. In summary, the four-step assay protocol can easily be adapted into a high throughput format to rapidly screen unknown inhibitors.

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“…1,7-11 Interesting objects also are methoxy substituted phenylalanines used as key inter mediates in the synthesis of proteinase inhibitors, that opens access to the new agents for cancer therapy. 12 In addition, (S) 3,4 dimethoxyphenylalanine deri vative 1 found its application in the synthesis of ber berine alkaloid, viz., (S) xylopinine (2), 13 it can be also used for the preparation of antiparkinsonian drug L DOPA (3, Scheme 1). 8,11, 14 The most efficient ligands used nowadays in asymmet ric hydrogenation are bidentate phosphines.…”

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confidence: 99%

Asymmetric hydrogenation of methyl (Z)-2-acetamido-3-(3,4-dimethoxyphenyl)acrylate catalyzed by Rh complexes with available amidophosphite ligands

et al. 2010

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A convenient express procedure for the preparation of methyl (Z ) 2 acetamido 3 (3,4 dimethoxyphenyl)acrylate was developed. Asymmetric hydrogenation of this substrate in the presence of rhodium catalysts involving synthetically available amidophosphite ligands was carried out, which is characterized by high enantioselectivity (to 99.5% ee) and complete conversion. An approach to the selective formation of cationic complexes containing two ligands of different nature in one coordination sphere of rhodium was suggested.

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Entry into a New Class of Potent Proteasome Inhibitors Having High Antiproliferative Activity by Structure-Based Design

Abstract: Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.

Cited by 55 publications

References 28 publications

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

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

Semi-high throughput method of measuring proteasome inhibition in vitro and in cultured cells

Asymmetric hydrogenation of methyl (Z)-2-acetamido-3-(3,4-dimethoxyphenyl)acrylate catalyzed by Rh complexes with available amidophosphite ligands

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