KEAP1 Binder Bifunctional Compounds for Protein Degradation
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Solution Overview
Problem
There is a limited range of E3 ligase recruiters available for protein degraders, restricting the scope of proteins that can be targeted for degradation, particularly due to the lack of effective KEAP1 ligase-targeting functionality, which is essential for degrading proteins like Nrf2 and others.
Innovation Solution
Development of novel bifunctional compounds that recruit targeted proteins to the KEAP1 E3 ligase complex for degradation, specifically designed with a KEAP1 Binding Group (KBG) and a Protein Binding Group (PBG) linked by a bivalent linker, facilitating the recruitment and degradation of proteins of interest.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If only a limited number of E3 ligase recruiters are used, then the device complexity is reduced, but the adaptability or versatility of protein targeting is restricted
Solution Approach 1:
The patent develops bifunctional compounds that can recruit multiple different E3 ligases (including KEAP1, VHL, and others) through a single molecular framework. The compound contains a KEAP1 binding motif that enables recruitment of the KEAP1-CUL3 E3 ligase complex, while the modular design allows the same core structure to target different E3 ligases, thereby expanding protein targeting versatility without proportionally increasing complexity
Solution Approach 2:
The bifunctional compound is divided into distinct functional modules: a KEAP1 binding motif (containing specific chemical groups that bind KEAP1), a linker region, and a protein of interest binding domain. This segmentation allows each module to be optimized independently while maintaining overall functionality, enabling the system to target multiple proteins through different E3 ligases
2Adaptability or versatility
If novel bifunctional compounds with KEAP1 binding motifs are developed, then the adaptability or versatility of protein degradation is improved, but the ease of manufacture decreases
Solution Approach 1:
The synthesis approach divides the bifunctional compound creation into separate steps: first establishing the core KEAP1 binding motif structure, then adding the protein-binding domain and linker through modular assembly. This segmented synthesis strategy reduces overall complexity by breaking down the manufacturing process into manageable stages with standardized intermediates
Solution Approach 2:
The patent employs standardized linker molecules and intermediate structures that serve as mediators between the KEAP1 binding motif and the protein-specific binding domain. These intermediary components can be pre-synthesized and stored, simplifying the final assembly process and reducing the need for complex de novo synthesis of each complete bifunctional compound
Data Source
AI summary
The present invention relates to tetrahydroisoquinoline compounds that are KEAP1 binders and their incorporation in bifunctional compounds which are capable of acting as proteolysis-targeting chimeras. The present invention also relates to processes for the preparation of these bifunctional compounds, and to their use in the treatment of diseases or disorders associated with proteins that may be degraded through the KEAP1 E3 ligase.