Macrocyclic Ras Inhibitors Using Cyclophilin A Ternary Binding
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Solution Overview
Problem
Current drug discovery efforts have been largely unsuccessful in targeting Ras proteins, which are undruggable and play a crucial role in approximately 30% of human cancers, highlighting the need for new molecular modalities to modulate their function.
Innovation Solution
Formation of a high-affinity three-component complex between Ras proteins and the widely expressed cytosolic chaperone cyclophilin A, creating a new binding pocket that sterically occludes interactions with downstream effector molecules, thereby inhibiting oncogenic signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional small molecule drugs are used to target Ras proteins, then the drug can bind to a functionally important pocket on the target protein, but Ras proteins are undruggable and lack accessible binding pockets for small molecules
Solution Approach 1:
The patent introduces a chaperone protein as an intermediary component that bridges the small molecule ligand and the Ras target protein. The chaperone binds to Ras and presents a binding interface for the small molecule, effectively mediating the interaction between the drug and the previously undruggable target. This resolves the contradiction by enabling small molecule binding to Ras through an intermediary chaperone protein rather than direct binding to Ras alone.
Solution Approach 2:
The patent creates a composite molecular system consisting of three components: the small molecule ligand, the chaperone protein, and the Ras target protein. This ternary complex forms a composite structure where each component contributes specific functions - the small molecule provides binding affinity, the chaperone provides the binding interface and structural framework, and Ras provides the therapeutic target. This composite approach enables drug binding to previously undruggable targets by combining multiple molecular modalities.
2Reliability
If a high affinity three-component complex is formed between synthetic ligand and Ras protein with chaperone, then a new binding pocket is created to inhibit Ras activity, but the device complexity increases from traditional two-component drug-target interaction
Solution Approach 1:
The patent segments the binding interaction into two distinct modules: the chaperone-Ras binding module and the small molecule-chaperone binding module. This segmentation allows each component to optimize its binding function independently - the chaperone is optimized for high affinity Ras binding, while the small molecule is optimized for chaperone binding. The segmented approach resolves the contradiction by distributing the binding functions across multiple components rather than requiring a single complex molecule to perform all functions.
Solution Approach 2:
The patent creates a nested structure where the small molecule ligand is bound to the chaperone protein, which in turn is bound to the Ras target protein. This nested arrangement forms a hierarchical complex where each component is embedded within the larger structure. The nesting resolves the contradiction by organizing multiple components in a hierarchical manner that maintains high overall affinity while managing complexity through structured organization of binding interfaces.
3Productivity
If extensive drug discovery efforts are applied to target Ras proteins using conventional approaches, then significant resources and time are invested, but no direct Ras-targeting drug is approved due to the undruggable nature of Ras
Solution Approach 1:
The patent inverts the conventional drug discovery approach by not attempting to bind the small molecule directly to Ras, but instead binding the small molecule to a chaperone that then binds to Ras. This inversion of the binding pathway resolves the contradiction by reversing the traditional approach - rather than drug→target directly, the pathway becomes drug→chaperone→target, thereby achieving Ras inhibition through an inverted binding mechanism that overcomes the undruggable barrier.
Solution Approach 2:
The chaperone protein serves as a mediator that enables drug discovery against Ras by providing an accessible binding interface for small molecules. This mediator approach resolves the contradiction between productivity and reliability by offering a new discovery pathway that maintains high success potential (through proven chaperone-Ras interaction) while improving productivity (by using accessible small molecule binding to the chaperone rather than direct Ras screening).
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
This approach effectively inhibits Ras proteins, offering a potential therapeutic strategy for treating cancers driven by Ras mutations.
Implementation Method 1
formation of a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins
Implementation Method 2
one way the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, they form is by steric occlusion of the interaction site between Ras and downstream effector molecules
Data Source
AI summary
The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.