Small molecules

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...

AI Technical Summary

Benefits of technology

[0058]Powders and sprays can contain, in addition to the PROTAC compounds of this invention, excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

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.

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