Macrocyclic Ras Inhibitors Using Cyclophilin A Tri-Complex Binding
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Solution Overview
Problem
Current small molecule drug discovery efforts have been largely unsuccessful in targeting 'undruggable' proteins like Ras, which are crucial in various human cancers, with no approved drugs directly inhibiting the 'on' form of Ras proteins.
Innovation Solution
Development of Ras inhibitors that form a high affinity tri-complex with Ras and cyclophilin A, creating a new binding pocket to sterically occlude interactions with downstream effectors, thereby inhibiting oncogenic signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If small molecule drugs are used to target proteins, then drug discovery is feasible for some proteins, but only about 10% of human proteins are targetable while the other 90% are considered undruggable
Solution Approach 1:
The patent introduces cyclophilin A as an intermediary protein that mediates the interaction between the small molecule inhibitor and Ras. The inhibitor does not directly bind to Ras but instead binds to cyclophilin A, which then interacts with Ras to form a ternary complex. This intermediary approach enables targeting of previously undruggable proteins by using a mediator protein to bridge the gap between the small molecule and the target protein.
2Reliability
If a high affinity tri-complex is formed between inhibitor and two proteins, then binding affinity is improved, but the mechanism becomes more complex compared to traditional single-protein binding
Solution Approach 1:
The patent merges the binding interactions of the inhibitor with cyclophilin A and the cyclophilin A-Ras interaction into a single ternary complex. By combining these two binding events into one integrated complex, the system achieves high affinity binding (improving reliability) while the complexity is managed through the natural interaction interface between cyclophilin A and Ras, which already exists in the cellular environment.
3Adaptability or versatility
If a new binding pocket is induced in Ras by forming a tri-complex, then selectivity for Ras(ON) is improved, but the structural changes required are more difficult to achieve
Solution Approach 1:
The patent employs preliminary action by using cyclophilin A to pre-organize the Ras protein into a conformation that exposes or creates a binding pocket for the inhibitor. Instead of requiring the inhibitor to directly induce structural changes in Ras (which would be difficult), the cyclophilin A binding event occurs first and prepares the Ras structure, making subsequent inhibitor binding feasible and selective for the Ras(ON) state.
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
The inhibitors effectively target Ras(ON), providing a therapeutic approach for Ras-related disorders and cancers by blocking oncogenic signaling pathways.
Implementation Method 1
the inhibitors of Ras described herein induce a new binding pocket in Ras by driving formation of a high affinity tri-complex between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA)
Implementation Method 2
one way the inhibitory effect on Ras is effected by compounds of the invention and the complexes 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.