N/O-Linked Degronimers for Selective Protein Degradation
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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 cancer and hematopoietic malignancies.
Innovation Solution
Development of Degronimers, which are compounds comprising Degrons that bind to E3 Ubiquitin Ligases like cereblon, linking them to Targeting Ligands to recruit target proteins for degradation via the ubiquitin-proteasome pathway, specifically targeting Ikaros or Aiolos for therapeutic intervention.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing technologies are used to harness the ubiquitin-proteasome pathway, then some protein degradation capability is achieved, but the detail and efficacy are insufficient for therapeutic applications
Solution Approach 1:
The degradation system is segmented into distinct functional modules: a targeting ligand that binds the target protein, a linker that connects the ligand to the degron, and a degron that binds the E3 ubiquitin ligase. This modular segmentation allows each component to be optimized independently while ensuring reliable therapeutic protein degradation through the ubiquitin-proteasome pathway.
2Reliability
If Degrons are linked to targeting ligands to recruit target proteins for degradation, then therapeutic efficacy is improved, but the molecular complexity of the compound increases
Solution Approach 1:
The patent merges the targeting ligand and degron into a single bifunctional compound called a Degronimer. This combining approach allows the compound to simultaneously perform target protein recognition and E3 ligase recruitment, achieving therapeutic protein degradation while reducing the need for separate molecular components compared to alternative approaches.
3Reliability
If specific proteins like Ikaros or Aiolos are targeted for degradation, then treatment of disorders like multiple myeloma and leukemia is improved, but the precision required for selective targeting increases difficulty
Solution Approach 1:
The E3 ubiquitin ligase (such as cereblon) serves as an intermediary that recognizes the degron moiety of the Degronimer and mediates the ubiquitination of the target protein. This intermediary mechanism enables highly selective targeting of specific proteins like Ikaros or Aiolos, as the E3 ligase-degron interaction provides the necessary precision for selective degradation of disease-causing proteins while sparing healthy proteins.
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 Degronimers effectively degrade target proteins, modulating their levels and activity, offering therapeutic benefits in treating disorders like multiple myeloma, leukemia, and other conditions by enhancing ubiquitination and proteasomal degradation.
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
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.