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Small molecules

a technology of ubiquitin ligase and small molecules, which is applied in the field of small molecules, can solve the problems of incomplete blockade of enzyme activity, ineffective e3 ligase inhibition, and failure to recapitulate genetic knockout or knockdown, so as to increase the flux of compound across the skin and control the delivery of compound

Inactive Publication Date: 2022-04-28
UNIVERSITY OF DUNDEE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

PROTACs achieve sub-stoichiometric catalytic activity, allowing for efficient degradation of E3 ubiquitin ligases at lower concentrations than traditional inhibitors, with enhanced selectivity and sustained cellular effects, capable of degrading target proteins effectively while avoiding compensatory feedback mechanisms.

Problems solved by technology

However, E3 ligases do not comprise deep and “druggable” active sites for binding to small molecules.
Blockade of E3 ligase activity therefore requires targeting of protein-protein interactions (PPIs), and the often extended, flat and solvent-exposed PPI surfaces make it a challenge for drug design.
This poses limitations, such as the need to use high inhibitor concentrations, which can lead to off-target effects and cytotoxicity, and incomplete blockade of enzyme activity.
As a result, E3 ligase inhibition may be ineffective or fail to recapitulate genetic knockout or knockdown.

Method used

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Embodiment Construction

[0100]While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.

[0101]To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

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Abstract

Compounds having the general structure A-L-B are presented wherein A and B are independently an E3 ubiquitin ligase protein binding ligand compound of formula 1A or 1B. Pharmaceutical compositions comprising these compounds and methods of use are also presented.

Description

FIELD OF THE INVENTION[0001]This invention relates to small molecule E3 ubiquitin ligase protein binding ligand compounds, and to their utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. This invention particularly relates to PROTACs capable of inducing auto-ubiquitination of E3 ubiquitin ligases and triggering their subsequent proteasomal degradation.BACKGROUND OF THE INVENTION[0002]E3 ubiquitin ligases are emerging as attractive targets for small-molecule modulation and drug discovery. E3s bring a substrate protein and ubiquitin in close proximity to each other to catalyze the transfer of a ubiquitin molecule to the substrate. Substrate ubiquitination can trigger different cellular outcomes, of which one of the best characterized is poly-ubiquitination and subsequent proteasomal degradation. The human genome comprises >600 predicted E3 ligases that play important roles in normal cellular physiology and dise...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D417/14
CPCC07D417/14C07K5/06191C07K5/06034C07K5/06165A61P35/00
Inventor CIULLI, ALESSIOMANIACI, CHIARAHUGHES, SCOTT J.TESTA, ANDREA
Owner UNIVERSITY OF DUNDEE
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