Bifunctional Compounds Degrade SMARCA and PB1 Proteins
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Solution Overview
Problem
Current treatments for diseases such as hyperplasia and cancers lack specificity and are unable to effectively target and modulate proteins like SMARCA and PB1, which are associated with various cellular processes.
Innovation Solution
Development of novel bifunctional compounds that recruit SMARCA2, SMARCA4, or PB1 proteins to E3 ubiquitin ligases for degradation or directly facilitate ubiquitination for degradation, thereby modulating their activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional treatments are used for diseases such as hyperplasia and cancers, then treatment coverage is provided, but specificity and effectiveness in targeting proteins like SMARCA and PB1 are lacking
Solution Approach 1:
The treatment approach is segmented into two functional components: a protein-binding moiety that provides specificity for target proteins (SMARCA/PB1) and a bivalent moiety that recruits E3 ubiquitin ligases for degradation. This segmentation allows each component to be optimized independently for its specific function.
Solution Approach 2:
The bifunctional compounds act as intermediary molecules that bridge the gap between the target protein and the E3 ubiquitin ligase system. These compounds mediate the interaction by simultaneously binding to the target protein and recruiting the ligase, enabling precise and effective protein degradation.
2Adaptability or versatility
If non-specific treatments are used, then broad disease coverage is achieved, but the ability to target and modulate specific proteins is lost
Solution Approach 1:
The platform approach creates universal bifunctional compounds that can be adapted for multiple disease indications by changing the protein-binding moiety. The same core structure with E3 ligase recruitment capability can target different proteins for different diseases, providing both specificity and versatility.
Solution Approach 2:
The invention utilizes parameter changes in the molecular structure, specifically modifying the protein-binding moiety while maintaining the conserved E3 ligase-binding bivalent moiety. This allows optimization of binding affinity and specificity for different target proteins across various diseases.
3Duration of action of moving object
If existing therapeutic agents are used, then general disease treatment is provided, but temporal control over protein expression cannot be achieved
Solution Approach 1:
The treatment system provides dynamic control over protein expression by introducing bifunctional compounds that can be administered at specific times to induce degradation of target proteins only when needed. This dynamic approach allows temporal control of protein levels in response to disease state or treatment requirements.
Solution Approach 2:
The E3 ubiquitin ligase recruitment mechanism ensures continuous degradation action once the bifunctional compound is introduced. The pathway maintains continuous useful action by continuously recruiting the ligase to degrade the target protein, providing sustained temporal control over protein expression.
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
The compounds effectively degrade SMARCA and/or PB1 proteins, offering a broad range of pharmacological activities and potential therapeutic benefits, including the treatment of cancers such as lung cancer.
Implementation Method 1
The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases
Implementation Method 2
synthetic small-molecule probes to induce proteasome-dependent degradation
Data Source
AI summary
The present invention provides compounds, compositions thereof, and methods of using the same.