Heterocyclic Cullin-RING Ligase Compounds for Protein Degradation
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Solution Overview
Problem
Current compounds struggle to induce ubiquitination and degradation of target proteins lacking hydrophobic binding pockets or inhibitory sites, such as MYC, RAS, or β-catenin, which are crucial for treating diseases like cancer and neurological disorders, due to limitations in binding mechanisms and pharmacological properties.
Innovation Solution
Development of novel compounds, such as those represented by formulae (I), (II), (III), and (IV), which act as molecular glues or PROTACs, capable of enhancing cullin-RING ubiquitin ligase activity to facilitate ubiquitination and degradation of target proteins by forming direct interactions with the cullin-RING ligase complex, independent of substrate receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional small molecule inhibitors are used to block protein activity, then the activity of the target protein is reduced, but the approach cannot effectively degrade target proteins lacking hydrophobic binding pockets or inhibitory sites
Solution Approach 1:
The patent employs cullin-RING ubiquitin ligase (CRL) as an intermediary system. Instead of directly binding to the target protein, the compound recruits CRL to the target protein, which then mediates ubiquitination and degradation. This intermediary approach allows degradation of target proteins that lack conventional drug-binding features, as the CRL system provides the necessary binding and catalytic functions.
Solution Approach 2:
The patent replaces the conventional small molecule-inhibitor mechanical binding system with a ubiquitin-proteasome degradation system. Rather than relying on direct competitive inhibition at hydrophobic pockets, the system uses ubiquitin conjugation followed by proteasomal degradation, substituting the mechanical binding mechanism with a biochemical degradation pathway that can target previously undruggable proteins.
2Reliability
If heterobifunctional degraders are designed to bind both target protein and E3 ligase, then targeted protein degradation is achieved, but the molecular weight increases and may impact pharmacology and bioavailability
Solution Approach 1:
The patent extracts and utilizes only the essential E3 ligase binding component (cullin-RING ubiquitin ligase) while eliminating the need for complex heterobifunctional design. By focusing on recruiting CRL specifically, the approach avoids combining multiple large functional domains into a single heterobifunctional molecule, thereby maintaining lower molecular weight while achieving degradation functionality.
Solution Approach 2:
The patent leverages the universal functionality of cullin-RING ubiquitin ligases, which can recognize and degrade multiple different target proteins through substrate recruitment. This universal system allows a single compound design strategy to target multiple proteins without requiring separate heterobifunctional molecules for each target, effectively reducing overall molecular complexity.
3Adaptability or versatility
If compounds are designed to induce ubiquitination through CRL recruitment, then previously undruggable proteins can be degraded, but the binding mechanism and pharmacological properties become more complex
Solution Approach 1:
The patent inverts the conventional approach by not trying to make the compound bind directly to the target protein, but rather making the target protein (or its complex) bind to the recruited CRL system. This inversion simplifies the compound design, as it only needs to provide the recruitment function rather than both target binding and degradation initiation functions.
Data Source
AI summary
The present invention relates to compounds with the ability to stimulate/induce ubiquitination of a target protein/target proteins. The compounds of the present invention may stimulate/induce ubiquitination of a target protein/target proteins; i.e. via degradation of a target protein/target proteins by the cullin-RING ubiquitin ligase (CRL). Such target protein/target proteins may be proteins involved in diseases, like cancer, metabolic disorder, infectious disease and/or neurological disorder. The invention also relates to the compounds and composition for use as medicaments as well as pharmaceutical compositions comprising these compounds. Particularly, the compounds of the present invention may degrade proteins associated with cancer, metabolic disorder, infectious disease and/or neurological disorder. Furthermore, the present invention relates the compounds for use as a medicament, such as for use in treating cancer, metabolic disorder, infectious disease and/or neurological disorder and to a method for treating a disease, such as cancer, metabolic disorder, infectious disease and/or neurological disorder, comprising administering the compound of the present invention.