Macrocyclic Ras Inhibitors via Cyclophilin A Ternary Complexes
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Solution Overview
Problem
Current drug discovery efforts have been largely unsuccessful in targeting Ras proteins, which are undruggable targets and play a crucial role in various human cancers, despite their significance in approximately 30% of all human cancers in the United States.
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 Ras activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional small molecule drugs are used to target Ras proteins, then the approach is simple and direct, but the drugs cannot effectively bind to Ras due to the lack of druggable pockets
Solution Approach 1:
The patent introduces cyclophilin A as an intermediary protein that mediates the binding between the small molecule compound and Ras. The compound first binds to cyclophilin A, which then interacts with Ras to form a ternary complex. This intermediary mechanism allows small molecules to indirectly target Ras despite the absence of traditional druggable pockets on Ras itself.
Solution Approach 2:
The invention transitions from direct one-to-one binding (compound-Ras) to a three-component complex (compound-cyclophilin A-Ras). This dimensional expansion from 1:1 to 1:2:1 complex allows the system to overcome the structural limitations of Ras by utilizing the binding interfaces of multiple proteins.
2Reliability
If a three-component complex is formed between the compound, cyclophilin A, and Ras, then binding effectiveness is improved, but the mechanism complexity increases
Solution Approach 1:
Cyclophilin A serves multiple functions in this system: it acts as a binding platform for the small molecule compound, serves as a bridge to Ras, and facilitates the formation of the inhibitory ternary complex. This multi-functionality of the intermediary protein simplifies the overall design compared to creating entirely new multi-component systems.
3Ease of manufacture
If the compound binds to Ras directly, then the mechanism is straightforward, but no effective binding pocket exists on Ras
Solution Approach 1:
The patent employs cyclophilin A as a mediator that provides the necessary binding interface for small molecules. Instead of attempting to design compounds that directly bind to the non-druggable Ras surface, the intermediary approach allows use of well-established small molecule-protein binding principles with cyclophilin A, while achieving Ras inhibition through the ternary complex.
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.