Macrocyclic Ras Inhibitors Using Cyclophilin A Ternary Binding
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Solution Overview
Problem
Current small molecule drug discovery efforts have been largely unsuccessful in targeting the vast majority of human proteins, known as 'undruggable' targets, including Ras proteins, which are crucial in various human cancers, with only two agents approved for K-Ras G12C mutant cancers.
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 oncogenic signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If small molecule drugs are used to target proteins, then the drug can bind to the target protein and modulate its activity, but only about 10% of human proteins are targetable by small molecules while the other 90% are refractory or intractable
Solution Approach 1:
The patent introduces a chaperone protein as an intermediary component that binds to the small molecule drug and the target protein simultaneously, forming a ternary complex. This mediator enables small molecules to indirectly target previously undruggable proteins by utilizing the chaperone's binding capability, thereby expanding the scope of targetable proteins from 10% to potentially include the 90% that were previously intractable.
2Reliability
If Ras proteins are targeted with small molecule drugs, then anticancer therapy can be achieved, but despite extensive drug discovery efforts over several decades, only two agents targeting K-Ras G12C mutant have been approved
Solution Approach 1:
The patent segments the drug-target interaction into two distinct binding events: first, the small molecule binds to the chaperone protein, and second, the chaperone-drug complex binds to the Ras protein. This segmentation allows optimization of each interaction independently and enables targeting of Ras mutants that cannot bind small molecules directly, thereby increasing the number of potential approved drugs for Ras-targeted therapy.
Solution Approach 2:
The chaperone protein serves as a mediator that bridges the small molecule drug and the Ras target protein. This intermediary approach overcomes the limitation of direct small molecule-Ras binding, enabling the development of multiple novel agents beyond the two currently approved K-Ras G12C inhibitors by leveraging the chaperone's ability to facilitate binding to various Ras mutants.
3Reliability
If a high affinity three-component complex is formed between synthetic ligand and two intracellular proteins, then a new binding pocket is induced in Ras that sterically occludes interaction with downstream effector molecules, but the complex requires formation of a ternary structure rather than simple binary binding
Solution Approach 1:
The ternary complex formation is segmented into distinct functional domains: the synthetic ligand binds to the chaperone protein's ligand-binding pocket, while the chaperone-Ras interface provides the second binding surface. This segmentation of binding events into separate modular interactions simplifies the design process despite the overall complexity of the ternary structure, as each binding interface can be optimized independently.
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
This approach effectively inhibits Ras proteins, providing a new mechanism to target undruggable proteins and potentially treat cancers driven by various Ras mutations.
Implementation Method 1
formation of a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A)
Implementation Method 2
induce a new binding pocket in Ras by driving formation of a high affinity tri-complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA)... steric occlusion of the interaction site between Ras and downstream effector molecules
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.