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Compounds for proteasome enzyme inhibition

A technology for compounds, drugs, applied in the therapeutic field based on enzyme inhibition, which can solve problems such as lack of specificity, stability or efficacy

Active Publication Date: 2007-09-26
安进生物医药(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] While there are many examples of small molecules used to inhibit proteasome activity, these compounds often lack the specificity, stability, or potency necessary to exploit proteasome action at the cellular and molecular levels

Method used

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  • Compounds for proteasome enzyme inhibition
  • Compounds for proteasome enzyme inhibition
  • Compounds for proteasome enzyme inhibition

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Embodiment Construction

[0015] The present invention relates to compounds useful as enzyme inhibitors. These compounds are generally useful for inhibiting enzymes with a nucleophilic group at the N-terminus. For example, the activity of enzymes or enzyme subunits containing an N-terminal amino acid having a nucleophilic group in the side chain, such as threonine, serine, or cysteine, can be successfully inhibited by the enzyme inhibitors described herein. The activity of enzymes or enzyme subunits having a non-amino acid nucleophilic group at the N-terminus, such as a protecting group or a sugar group, can also be successfully inhibited by the enzyme inhibitors described herein.

[0016] While not wishing to be bound by any particular theory, it is believed that the N-terminal nucleophilic group of Ntn forms a covalent adduct with the epoxy functionality of the enzyme inhibitors described herein. For example, in the β5 / Pre2 subunit of the 20S proteasome, it is generally believed that the N-terminal ...

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Abstract

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Patent Application 60 / 599401, filed August 6, 2004, and U.S. Provisional Patent Application 60 / 610001, filed September 14, 2004, and filed April 14, 2005 A continuation-in-part of US Patent Application 11 / 106879. The entire disclosures of all of the above applications are incorporated by reference into this application. technical field [0003] The present invention relates to compounds and methods for enzyme inhibition. The invention particularly relates to therapeutic methods based on enzyme inhibition. Background of the invention [0004] In eukaryotes, protein degradation is primarily mediated through the ubiquitin pathway, in which the target protein to be destroyed is linked to the 76 amino acid polypeptide ubiquitin. Once attached to target proteins, ubiquitinated proteins serve as substrates for the 26S proteasome, a multicatalytically functional protease that cleaves proteins...

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Application Information

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IPC IPC(8): C07K5/087C07K5/103A61K38/07C07K5/02A61K38/06
Inventor M·S·史密斯G·J·莱迪
Owner 安进生物医药(上海)有限公司
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