Macrocyclic Ligand Induces Ras Binding Pocket
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current drug discovery efforts have been largely unsuccessful in targeting Ras proteins, which are implicated in approximately 30% of human cancers, due to their refractory nature to small molecule modulation.
Innovation Solution
The formation of a high affinity three-component complex between a synthetic ligand and Ras protein and cyclophilin A, inducing a new binding pocket in Ras, thereby inhibiting its activity through steric occlusion of downstream effector molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule drugs bind to target protein pockets to modulate activity, then drug efficacy is achieved, but only about 10% of human proteins are targetable by this approach
Solution Approach 1:
The patent employs cyclophilin A as an intermediary protein that does not directly interact with Ras under normal physiological conditions. The synthetic ligand forms a ternary complex by bridging Ras and cyclophilin A, enabling indirect modulation of Ras activity. This intermediary approach allows targeting of previously undruggable Ras proteins through a different mechanism than direct small molecule binding.
2Reliability
If Ras proteins are targeted with conventional small molecule inhibitors, then cancer therapy is attempted, but Ras remains refractory to such modulation
Solution Approach 1:
The patent segments the inhibition mechanism into two separate interactions: (1) the synthetic ligand binds to a newly formed binding pocket on Ras, and (2) the same ligand simultaneously interacts with cyclophilin A. This segmentation allows the system to overcome Ras refractoriness by distributing the binding requirements across two proteins rather than demanding a single high-affinity binding site on Ras.
Solution Approach 2:
The patent creates a composite ternary complex system comprising Ras, cyclophilin A, and the synthetic ligand. This composite structure leverages the properties of all three components: Ras provides the oncogenic signaling function, cyclophilin A provides structural stability and cellular abundance, and the synthetic ligand provides selective binding and inhibition capability.
3Reliability
If a ternary complex is formed between synthetic ligand, Ras, and cyclophilin A, then new binding pocket is induced in Ras, but device complexity increases
Solution Approach 1:
The synthetic ligand performs multiple functions simultaneously: (1) it binds to Ras to induce conformational changes and create a new binding pocket, (2) it binds to cyclophilin A to stabilize the complex, and (3) it sterically occludes downstream effector molecules like RAF and PI3K. This multi-functionality reduces the need for separate molecules for each function, thereby managing complexity while achieving high inhibition specificity.
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 protein activity, providing a potential therapeutic strategy for cancers driven by Ras mutations, which have been challenging to treat with existing drugs.
Implementation Method 1
formation of a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A)
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, such as RAF and PI3K
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.