Macrocyclic Ras Inhibitors Using Cyclophilin-Mediated 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 various human cancers, despite their involvement in approximately 30% of all human cancers in the United States.
Innovation Solution
Formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins, Ras and cyclophilin A, creating a new binding pocket that sterically occludes the interaction site between Ras and 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 drugs can bind to functionally important pockets on target proteins, 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 binds to Ras and facilitates the binding of the small molecule ligand. The chaperone acts as a mediator between the undruggable Ras target and the small molecule drug, enabling inhibition of Ras activity despite the absence of traditional drug-binding pockets on Ras itself
Solution Approach 2:
The invention creates a composite inhibitory complex consisting of multiple components: the small molecule ligand, the chaperone protein, and the Ras target protein. This composite approach combines the advantages of small molecule drugs (oral availability, stability) with the binding capability of protein-chaperone interactions to achieve effective Ras inhibition
2Reliability
If a high affinity three-component complex is formed between synthetic ligand and intracellular proteins Ras and cyclophilin A, then a new binding pocket is created and oncogenic signaling is inhibited, but the device complexity increases
Solution Approach 1:
The patent merges the functions of multiple components into a single inhibitory complex. The small molecule ligand, chaperone protein, and Ras target are combined into a unified three-component complex that works together to achieve inhibition, with each component contributing a specific function to the overall mechanism
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.