BCL9/β-Catenin Small Molecules Balancing Affinity and Permeability
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Solution Overview
Problem
There is an urgent need for small molecule compounds that can effectively target the BCL9/β-catenin interaction with high affinity and good cell membrane permeability, as current inhibitors are limited in this area.
Innovation Solution
Development of a new class of small molecule compounds, as represented by specific chemical structures in Formula I and II, designed to target the BCL9/β-catenin interaction, with various substituents and functional groups to enhance targeting affinity and membrane permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide inhibitors are used to target BCL9/β-catenin interaction, then targeting affinity can be achieved, but cell membrane permeability deteriorates
Solution Approach 1:
The patent transforms the peptide inhibitor into a small molecule compound by fundamentally changing the chemical structure parameters. The compound of Formula I features a non-peptidic core structure with specific functional groups (amino group, hydroxyl group, carbonyl group) and molecular weight控制在200-500 Da, which fundamentally alters its physical and chemical properties to achieve both high affinity binding and excellent cell membrane permeability
Solution Approach 2:
The small molecule compound integrates multiple functional groups (amino, hydroxyl, carbonyl) and structural elements (aromatic rings, aliphatic chains) into a single composite molecular structure. This composite design allows the molecule to simultaneously engage in multiple interactions with the BCL9/β-catenin interface while maintaining optimal pharmacokinetic properties including membrane permeability
2Ease of operation
If non-peptide small molecule inhibitors are developed, then cell membrane permeability is improved, but targeting affinity deteriorates
Solution Approach 1:
The small molecule compound of Formula I features localized functional groups positioned at specific spatial coordinates within the molecular structure. The amino group, hydroxyl group, and carbonyl group are strategically positioned to form specific interactions with residues at the BCL9/β-catenin interface, while the core structure maintains hydrophobic character for membrane permeability. This local optimization of functional groups enables simultaneous achievement of high affinity and good permeability
3Reliability
If inhibitors are designed with high targeting affinity, then BCL9/β-catenin interaction is effectively blocked, but molecular complexity increases
Solution Approach 1:
The patent extracts only the essential functional elements needed for BCL9/β-catenin binding from complex peptide structures. The small molecule compound contains specifically selected functional groups (amino, hydroxyl, carbonyl) and structural motifs that are sufficient for high-affinity binding, eliminating unnecessary complex peptide backbones and side chains. This extraction results in a simplified molecular structure with controlled complexity that maintains high targeting affinity
Data Source
AI summary
Provided in the present invention is a compound containing a 2-methyl-2-(3-(piperidin-3-yl)phenoxy)-2-methylpropanamide skeleton. Specifically, provided in the present invention is a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof. The compound of formula I or formula II of the present invention has an excellent ability to inhibit BCL9/β-catenin interaction.