Macrocyclic Ras Inhibitors Using Cyclophilin-Induced Binding Pockets
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Solution Overview
Problem
Current small molecule drug discovery efforts have been largely unsuccessful in targeting 'undruggable' proteins, such as Ras proteins, which are implicated in approximately 30% of human cancers, due to their lack of a functionally important pocket for binding.
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 like RAF and PI3K, using compounds with specific structural features.
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 refractory or intractable
Solution Approach 1:
The patent introduces a three-component complex consisting of a small molecule drug, a chaperone protein, and a target protein (Ras). The chaperone protein acts as an intermediary that bridges the small molecule and the undruggable target, enabling drug discovery for previously intractable proteins by creating a new binding interface through induced fit mechanisms
Solution Approach 2:
The invention creates a composite drug system where a small molecule compound is combined with a chaperone protein to form a three-component complex. This composite approach allows the system to overcome the limitations of small molecules alone by leveraging the chaperone's ability to induce binding pockets in undruggable targets
2Reliability
If Ras proteins are targeted directly with small molecules, then oncogenic signaling could be inhibited, but Ras proteins are undruggable and no direct targeting drug has been approved despite extensive efforts
Solution Approach 1:
The chaperone protein serves as a mediator that enables small molecule binding to Ras proteins. The chaperone induces conformational changes in Ras that create accessible binding pockets, making the undruggable target druggable through this intermediary mechanism
Solution Approach 2:
The chaperone protein performs preliminary action by binding to Ras and inducing a conformational change that pre-creates a binding pocket before the small molecule drug can interact with the target. This preliminary structural preparation makes subsequent drug binding feasible
3Adaptability or versatility
If a three-component complex is formed between a synthetic ligand and two intracellular proteins, then a new binding pocket is induced in Ras, but this requires proteins that do not interact under normal physiological conditions
Solution Approach 1:
The system exploits dynamic conformational changes in the chaperone-Ras complex. The chaperone induces transient conformational states in Ras that create binding pockets not present in the native physiological state. This dynamic approach allows the formation of non-physiological but therapeutically useful protein-protein-ligand interactions
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.