mTORC2-Selective Screening for Metabolic Disorder Treatment
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Solution Overview
Problem
Current treatments for type 2 diabetes, particularly those targeting insulin resistance and glucose uptake, often come with side effects such as promoting cancer and obesity due to the stimulation of Akt, which complicates glucose metabolism regulation.
Innovation Solution
Stimulating mTORC2 to increase glucose uptake without activating Akt, using compounds that selectively activate mTORC2 in peripheral tissues, thereby reducing the need for insulin and minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If insulin or insulin-mimetic drugs are used to treat type 2 diabetes, then glucose uptake is improved, but side effects such as cancer promotion and obesity occur due to Akt stimulation
Solution Approach 1:
The patent segments the mTOR signaling pathway into two distinct complexes: mTORC1 and mTORC2. By selectively targeting mTORC2 with compounds that do not activate Akt, the invention isolates the beneficial glucose uptake effect from the harmful side effects associated with Akt stimulation, thereby resolving the technical contradiction between improved glucose uptake and reduced side effects.
Solution Approach 2:
The patent introduces mTORC2 as an intermediary mediator between glucose uptake regulation and Akt activation. By using mTORC2-selective compounds as intermediaries, the invention achieves glucose uptake enhancement without directly stimulating Akt, thus avoiding the harmful side effects of cancer promotion and obesity while maintaining the therapeutic benefit.
2Productivity
If conventional treatments targeting insulin signaling are used, then glucose homeostasis is improved, but the insulin pathway becomes down-regulated or desensitized
Solution Approach 1:
Instead of targeting the insulin receptor and upstream signaling components (the conventional approach that leads to down-regulation), the patent inverts the strategy by targeting mTORC2 downstream in the pathway. This alternative entry point allows glucose uptake enhancement without repeatedly stimulating the insulin receptor, thereby preventing desensitization and maintaining pathway reliability.
Solution Approach 2:
The patent extracts the mTORC2 component from the overall insulin signaling pathway and targets it specifically with selective compounds. By taking out mTORC2 as a separate therapeutic target, the invention bypasses the insulin receptor and upstream components, avoiding their down-regulation while still achieving the desired glucose uptake effect.
3Productivity
If Akt is stimulated to increase glucose uptake, then metabolic control is improved, but fat incorporation in fat, liver and skeletal muscle increases
Solution Approach 1:
The patent segments the mTOR signaling into mTORC1 and mTORC2, and specifically targets mTORC2 to achieve glucose uptake without activating Akt. This segmentation allows selective activation of glucose uptake pathways while avoiding the lipid metabolism effects mediated by Akt, thereby resolving the contradiction between improved glucose uptake and reduced fat incorporation.
Solution Approach 2:
The patent uses mTORC2 as an intermediary to achieve glucose uptake enhancement without directly activating Akt. By introducing mTORC2-selective compounds as intermediaries, the invention decouples glucose uptake from fat incorporation, allowing one benefit without the other's harmful effects.
Data Source
AI summary
A method of screening for a candidate compound for the treatment of a condition involving dysregulation of metabolism in a mammal, said method comprising bringing a compound into contact with at least one population of cells, comprising cells that express mTOR and Akt and that are capable of activating mTORC2 and Akt; determining mTORC2 activity and Akt activity in cells brought into contact with the compound, and identifying the candidate compound based on the determined mTORC2 activity and Akt activity. A kit for use in such a method of. A compound for use in a method of treatment of a condition involving dysregulation of metabolism in a mammal, and a method of treatment of such a condition.