Degronimer Small Molecules for Selective Protein Degradation
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Solution Overview
Problem
Existing technologies lack sufficient detail and efficiency 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 target proteins like Ikaros or Aiolos for degradation via the ubiquitin-proteasome pathway, using compounds with specific chemical structures to enhance interaction and ubiquitination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptides are used as ubiquitination recognition elements, then selective ubiquitination can be achieved, but oral drug administration becomes difficult
Solution Approach 1:
The patent changes the chemical parameters of the recognition element from peptide to small molecule, transforming it from a macromolecule suitable for injection to a low-molecular-weight compound suitable for oral administration, while maintaining its ability to bind E3 ligase and induce selective ubiquitination
Solution Approach 2:
The patent replaces complex, difficult-to-administer peptide molecules with simpler, orally-available small molecule compounds that can be easily manufactured and administered, sacrificing some molecular complexity for dramatically improved pharmacokinetic properties
2Reliability
If standard methods for drug discovery are used to screen for small molecules binding to ligase, then ubiquitination recognition elements can be identified, but the process lacks sufficient detail and efficiency
Solution Approach 1:
The patent performs preliminary structural optimization and screening based on known E3 ligase binding motifs before conducting full-scale drug discovery screens, pre-filtering candidates based on their ability to mimic natural ligand interactions and thereby increasing overall screening efficiency and reducing false positives
Solution Approach 2:
The patent implements iterative feedback loops where screening results inform structural optimization, which in turn refines screening criteria, creating a cycle of continuous improvement that increases both the detail and efficiency of the drug discovery process
3Reliability
If proteins are targeted for degradation via the ubiquitin-proteasome pathway, then cellular homeostasis can be restored, but defective proteasomal degradation is linked to various clinical disorders
Solution Approach 1:
The patent introduces small molecule compounds as intermediaries that bridge the target protein and E3 ligase, facilitating their interaction and enabling controlled degradation of disease-causing proteins through the ubiquitin-proteasome pathway, thereby restoring cellular homeostasis in disorders where proteasomal degradation is defective
Solution Approach 2:
The patent converts the harmful accumulation of misfolded or excess proteins that cause clinical disorders into a beneficial therapeutic effect by harnessing the cell's own ubiquitin-proteasome degradation machinery to eliminate these pathogenic proteins and restore normal cellular function
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
Effectively degrades targeted proteins, reducing their levels to treat disorders like multiple myeloma, leukemia, and other hematopoietic malignancies, and modulate transcriptional regulation, offering therapeutic benefits.
Implementation Method 1
bifunctional compounds and methods therefor that recruit a Targeted Protein to an E3 Ubiquitin Ligase for degradation
Implementation Method 2
Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation
Implementation Method 3
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.