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Proteasome inhibitors and uses thereof

a technology of proteasomes and inhibitors, applied in the field of proteasome inhibitors, can solve problems such as failure to predict the inhibitory activity of live cells

Inactive Publication Date: 2012-04-05
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]According to an aspect of some embodiments of the present invention there is provided a method of treating a disease in which inhibiting of a proteasome is advantageous, the method comprising administering to the subject a therapeutically effective amount of a compound which binds to a proteasome of

Problems solved by technology

Such assays may, in principle, be adapted to high-throughput screens, yet they may fail to predict the inhibitory activity in live cells.

Method used

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  • Proteasome inhibitors and uses thereof

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[0217]Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.

[0218]Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, biochemical, microbiological and recombinant DNA techniques. Such techniques are thoroughly explained in the literature. See, for example, “Molecular Cloning: A laboratory Manual” Sambrook et al., (1989); “Current Protocols in Molecular Biology” Volumes I-III Ausubel, R. M., ed. (1994); Ausubel et al., “Current Protocols in Molecular Biology”, John Wiley and Sons, Baltimore, Md. (1989); Perbal, “A Practical Guide to Molecular Cloning”, John Wiley & Sons, New York (1988); Watson et al., “Recombinant DNA”, Scientific American Books, New York; Birren et al. (eds) “Genome Analysis: A Laboratory Manual Series”, Vols. 1-4, Cold Spring Harbor Laboratory Press, New York (1998); methodologies as set...

example i

Discovery of Novel Proteasome Inhibitors Using a High-Content Cell-Based Screening System

[0219]Materials and Methods

[0220]DNA constructs, generation of a stable reporter cell line and transient transfection: To construct a YFP-tagged Proteasome Inhibitor Reporter (PIR) protein, cDNA encoding a full-length human p53 R175H mutant was amplified by PCR from a cDNA clone, and three consecutive lysine residues in the bipartite Nuclear Localization Signal (NLS) were replaced with alanines by PCR-based, site-directed mutagenesis [Higuchi R, et al., (1988) Nucleic Acids Res 16: 7351-7367; Ho SN, et al (1989) Gene 77: 51-59]. The DNA fragment was cloned into the BglII and NotI sites of pLPCX retroviral vector (Clontech) in-frame to the N-terminus of the yellow fluorescent protein (YFP), using the NotI / ClaI restriction sites. The PIR protein was expressed in an H1299 non-small cell lung carcinoma cell line, following retroviral infection, and the cells were cultured in RPMI 1640 medium contain...

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Abstract

A method of treating a disease in which inhibiting of a proteasome is advantageous is provided. The method comprises administering to the subject a therapeutically effective amount of a compound which binds to a proteasome of a cell, the compound comprising a copper bound to a ligand, the ligand being configured such that upon binding to the proteasome, the copper interacts with cysteine 31 of a Beta2 subunit of the proteasome and further interacts with cysteine 118 of a Beta3 subunit of the proteasome, thereby treating the disease. Additional novel proteasome inhibitors are also provided as well as methods of identifying proteasome inhibitors.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001]The present invention, in some embodiments thereof, relates to proteasome inhibitors and uses thereof.[0002]The proteasome is the major proteolytic complex, responsible, in eukaryotic cells, for the degradation of a multitude of cellular proteins. This multi-protein complex, present in both the cytoplasm and the nucleus, catalyzes the ATP-dependent proteolysis of short-lived regulatory proteins, as well as the rapid elimination of damaged and abnormal proteins. The 26S proteasome is a large complex of ˜2.5 MDa. Based on biochemical analyses, this complex can be dissociated into two functionally distinct subcomplexes, the 20S core particle (CP) which is the proteolytic component, and the 19S regulatory particle (RP), that is responsible for recognizing, unfolding, and translocating polyubiquitinated substrates into the 20S CP, where they are degraded.[0003]The 20S CP is a 670 kDa barrel-shaped protein complex made up of four stacked, seven-m...

Claims

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Application Information

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IPC IPC(8): A61K31/60C07H21/04C12N5/00A61P25/28A61K31/522A61K31/555A61P35/00A61P29/00C07K14/00C12Q1/02
CPCA61K31/47A61K31/522A61K31/555A61K31/60A61K33/34A61K31/52C07K2319/40C07K2319/60C12N9/6421C12Y304/25001G01N33/5035C07K14/4746A61P25/28A61P29/00A61P35/00
Inventor LAVELIN, IRINAROTTER, VARDAOREN, MOSHENAVON, AMIKAM, ZVIGEIGER, BENJAMIN
Owner YEDA RES & DEV CO LTD
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