Biphenyldicarboxamide α-Helix Mimetics for Selective PPI Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing α-helix mimetics struggle to replicate the conformational diversity of naturally occurring α-helices at protein-protein interaction interfaces and lack metabolic stability and bioavailability, making them ineffective for selectively targeting specific proteins.
Innovation Solution
Development of a scaffold-based α-helix mimetics with Formula I, capable of presenting substituents in various conformations to mimic the hydrophobic helical surface of BH3 domains in pro-apoptotic Bcl-2 family proteins, enhancing selective inhibition of anti-apoptotic members.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If rigid non-peptidic scaffolds are used to create α-helix mimetics, then structural stability is improved, but conformational adaptability deteriorates
Solution Approach 1:
The patent introduces flexible linkers between the rigid scaffold and side chains, allowing the mimetic to dynamically adjust its conformation. This enables the structure to adapt to different binding partners while maintaining the stability provided by the rigid core scaffold.
Solution Approach 2:
The patent applies different rigidity characteristics to different parts of the molecule: the core scaffold remains rigid for structural stability, while the linkers and side chains provide flexibility for conformational adaptation. This local differentiation resolves the contradiction between stability and adaptability.
2Shape
If ideal α-helix conformation is enforced by the scaffold, then structural definition is improved, but biological relevance deteriorates
Solution Approach 1:
The patent allows the α-helix mimetic to dynamically adjust from an ideal conformation to conformations that better match naturally occurring helices in proteins. This dynamic adjustment maintains structural definition while improving biological relevance by accommodating conformational variations found in real protein interfaces.
3Adaptability or versatility
If short peptides are used to target PPIs, then selectivity is improved, but metabolic stability deteriorates
Solution Approach 1:
The patent creates a simplified copy of the peptide structure using rigid non-peptidic scaffolds that replicate the essential α-helical features and binding capabilities. This copy maintains the selectivity of peptide-based PPI inhibitors while achieving superior metabolic stability through the use of chemically stable scaffold materials.
Data Source
AI summary
In one aspect, the disclosure relates to a for α-helix mimetics that can replicate the α-helices found at protein protein interaction (PPI) interfaces and can selectively discriminate cognate proteins in PPIs. In one aspect, the scaffolds have Formula Iwherein each of X1-X8 is individually selected from H, OR1, NR1R2, SR1, or PR1R2;wherein each of Y1-Y2 is individually selected from H, CO2R1, C(═O)NR1R2, C(═O)R1, OR1, NR1R2, SR1, or PR1R2; andwherein each of R1 and R2 is individually selected from H, or optionally substituted linear or branched C1-C20 alkyl, C3-C20 aryl, linear or branched C2-C20 alkenyl, linear or branched C2-C20 alkynyl, or C3-C20 arylalkyl.Also disclosed are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating cancer using the compounds.