Ras Inhibitors Using Cyclophilin A Ternary Complexes
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Solution Overview
Problem
Current drug discovery efforts have been largely unsuccessful in targeting the 'on' form of Ras proteins, which are crucial in various human cancers, as they are considered undruggable by small molecules, limiting the development of effective anticancer therapies.
Innovation Solution
Formation of a high-affinity three-component complex between Ras proteins and a 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 small molecule drugs are used to target Ras proteins, then the approach is simple and direct, but Ras proteins are considered undruggable and cannot be effectively targeted
Solution Approach 1:
The patent introduces an intermediary component (the heterobifunctional compound) that mediates the interaction between the drug and the target protein. The compound contains a first moiety that binds to the target protein and a second moiety that binds to the chaperone, effectively bridging the gap and enabling inhibition of previously undruggable targets
Solution Approach 2:
The invention creates a composite molecular structure by joining two different binding moieties into a single heterobifunctional compound. This composite structure allows the molecule to simultaneously engage with both the target protein and the chaperone, achieving a function that neither moiety could accomplish alone
2Reliability
If a high affinity three-component complex is formed between synthetic ligand and intracellular proteins, then new binding pockets are created and oncogenic signaling is inhibited, but the device complexity increases
Solution Approach 1:
The compound is segmented into two distinct functional moieties: a first moiety designed to bind the target protein and a second moiety designed to bind the chaperone. This segmentation allows each part to optimize its binding to the respective target while working together as a unified therapeutic agent
Solution Approach 2:
The chaperone protein acts as an intermediary that facilitates the formation of the ternary complex. By binding to both the synthetic ligand and the target protein, the chaperone mediates the interaction and stabilizes the complex, enabling effective inhibition without requiring direct high-affinity binding between the ligand and target protein
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.