E2-Binding PROTAC Compositions to Avoid E3 Ligase Resistance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current PROTACs are limited by their reliance on E3 ubiquitin ligases, which are susceptible to mutations, leading to acquired resistance in clinical applications.
Innovation Solution
Designing PROTAC compounds that recruit target proteins to ubiquitin conjugating enzymes (E2s) like UBE2K, utilizing an E2 enzyme binding moiety, a target protein binding moiety, and a linker to facilitate ubiquitination and degradation independently of E3 ligases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PROTACs use E3 ubiquitin ligases as targets, then protein degradation can be achieved, but resistance develops due to high mutation frequency in E3 ligases
Solution Approach 1:
The patent extracts the E3 ligase component from the PROTAC mechanism and replaces it with E2 ubiquitin conjugating enzymes. By removing the dependency on E3 ligases, the system eliminates the source of resistance while maintaining the essential protein degradation function through E2 enzyme-mediated ubiquitination.
Solution Approach 2:
The patent changes the target enzyme parameter from E3 ligase to E2 enzyme, leveraging the low mutation frequency of E2 enzymes compared to E3 ligases. This parameter change fundamentally alters the resistance profile of the PROTAC system, making it more reliable for clinical applications.
2Productivity
If PROTACs are designed to bind E3 ligases, then target protein degradation is achieved, but the system becomes vulnerable to acquired resistance
Solution Approach 1:
The patent removes the E3 ligase binding component from the PROTAC structure and replaces it with E2 enzyme binding moieties. This extraction eliminates the vulnerability to acquired resistance while preserving the ability to efficiently degrade target proteins through E2-mediated ubiquitination.
3Reliability
If E3 ligases are used as targets in PROTACs, then protein modulation is achieved, but mutation susceptibility leads to treatment failure
Solution Approach 1:
The patent changes the target parameter from E3 ligase (high mutation frequency) to E2 enzyme (low mutation frequency). This parameter change fundamentally improves treatment durability by selecting a target with inherently lower mutational susceptibility, thereby reducing the likelihood of treatment failure.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach reduces the risk of resistance by leveraging the low mutation frequency of E2 enzymes, effectively degrading target proteins and treating diseases such as cancer.
Implementation Method 1
compounds and compositions which function to recruit target proteins to E2 enzyme (e.g., UBE2K) for ubiquitination and subsequent degradation
Data Source
AI summary
Provided herein are E2 binding PROTACS and uses thereof.