Degronimer E3 Ligase Targeting for Protein Degradation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing technologies lack sufficient detail and efficacy in harnessing the ubiquitin-proteasome pathway for therapeutic protein degradation, particularly in targeting specific proteins for clinical disorders such as Alzheimer's, Parkinson's, Huntington's disease, muscular dystrophies, cardiovascular disease, and cancer.
Innovation Solution
Development of Degronimers and Degrons that bind to E3 Ubiquitin Ligases, specifically cereblon, to enhance the ubiquitination and degradation of proteins like Ikaros and Aiolos, using compounds with specific structures (Formulas I-IV) to modulate their activity and levels, thereby treating associated disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing ubiquitin-proteasome pathway technologies are used, then protein degradation can be achieved, but the specificity and efficacy for targeting clinical disorder proteins is insufficient
Solution Approach 1:
The patent introduces an E3 ubiquitin ligase as an intermediary component that specifically recognizes and binds to degron sequences on target proteins. This intermediary mechanism enables precise targeting of specific proteins (such as Ikaros and Aiolos in multiple myeloma) while maintaining high degradation efficacy through the natural ubiquitin-proteasome pathway, resolving the contradiction between targeting specificity and degradation efficacy
Solution Approach 2:
The patent modifies the target proteins by introducing or exposing specific degron sequences (parameter change in protein structure), which creates high-affinity binding sites for E3 ligases. This parameter change enables selective recognition and degradation of specific disease-causing proteins while leaving other proteins unaffected, thereby achieving both high specificity and efficacy
2Adaptability or versatility
If broad-spectrum protein degradation is applied, then multiple proteins can be degraded, but the ability to specifically target proteins associated with particular clinical disorders is reduced
Solution Approach 1:
The patent segments the protein degradation process into distinct functional modules: (1) E3 ubiquitin ligase with specific substrate recognition capability, (2) degron sequences that can be selectively introduced or exposed on different target proteins, and (3) the ubiquitin-proteasome degradation machinery. This segmentation allows the same E3 ligase system to be adapted for degrading different disease-associated proteins by simply changing the degron sequence, thereby maintaining both versatility and specificity
Solution Approach 2:
The patent employs a universal E3 ubiquitin ligase system (such as cereblon) that can recognize and degrade multiple different target proteins through their respective degron sequences. This universal platform can be applied to treat various clinical disorders including multiple myeloma, lymphomas, and other cancers by targeting different disease-causing proteins with the same core degradation machinery, achieving both broad adaptability and disease-specific precision
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 targeted proteins, reducing their levels and modulating transcriptional regulation, offering therapeutic benefits for hematopoietic malignancies, immune disorders, and other conditions by enhancing the ubiquitin-proteasome pathway's therapeutic potential.
Implementation Method 1
Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation
Implementation Method 2
the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins
Data Source
Figure 1A
Figure 1B
Figure 1C~1D
AI summary
This invention provides Degronimers that have E3 Ubiquitin Ligase targeting moieties (Degrons) that can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, and methods of use and compositions thereof as well as methods for their preparation. The invention also provides Degrons that can be used to treat disorders mediated by cereblon or an Ikaros family protein, and methods of use and compositions thereof as well as methods for their preparation.