USP14-Directed Proteolytic Chimeras for E3-Independent CERT Degradation
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Solution Overview
Problem
Existing proteolytic targeting chimeras (Protacs) face limitations such as restricted E3-ligases, poor solubility of ligands, and ubiquitylation requirements, making them ineffective in certain cases, and there is a need for a mechanism to target proteins like CERT independently of E3 ligases for cancer treatment.
Innovation Solution
Development of compounds that interact with proteasomal-associated factor Usp14 and CERT, bypassing E3 ligases, to induce the degradation of CERT directly at the 26S proteasome, using a novel chimera approach.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If E3-based Protacs are used for targeted protein degradation, then protein degradation can be achieved, but the approach is limited by reduced number of E3-ligases, poor solubility of ligands, and ubiquitylation requirements
Solution Approach 1:
Instead of using E3 ligases to recruit substrates to the proteasome (conventional Protac approach), the invention inverts the mechanism by using USP14 (a proteasomal-associated factor) to directly recruit and degrade substrates at the proteasome without requiring E3 ligase-mediated ubiquitylation. This is achieved through chimeric molecules that bind both USP14 and the target protein, enabling ubiquitin-independent degradation.
Solution Approach 2:
The invention introduces USP14 as an intermediary component in the degradation pathway. The chimeric molecules contain a USP14-binding domain that mediates recruitment of the complex to the proteasome, replacing the conventional E3 ligase intermediary role. This intermediary approach bypasses the limitations of E3 ligase availability and ubiquitylation requirements.
2Reliability
If ubiquitylation is required for Protac efficiency, then substrate recruitment can be achieved, but proper levels and activation state of ligase and accessibility of lysine residues are required
Solution Approach 1:
The invention extracts the ubiquitylation step from the degradation pathway by using USP14-mediated ubiquitin-independent substrate recruitment. This removes the dependency on E3 ligase activation states and lysine residue accessibility, simplifying the mechanism while maintaining effective substrate recruitment to the proteasome.
3Adaptability or versatility
If diverse degradation mechanisms are developed (Hytacs, Autacs, Lytacs), then alternative targeting modes are available, but the complexity of the system increases
Solution Approach 1:
The invention creates a universal degradation platform based on USP14 that can target multiple substrates without requiring different mechanistic approaches. The chimeric molecule design allows a single USP14-based mechanism to replace multiple specialized systems (Hytacs, Autacs, Lytacs), reducing overall system complexity while maintaining versatility through the modular nature of the chimeric constructs.
Data Source
Figure 1A~1C
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Figure 3A~3E
AI summary
USP14 inhibitors of formula I, wherein the meanings for the various substituents are as disclosed in the description, for use as a medicament and, particularly for the treatment of a cancer related to CERT.