Rapamycin Analogs for Selective mTORC1 and mTORC2 Inhibition
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Solution Overview
Problem
Current mTOR inhibitors, such as Rapamycin, are incomplete in inhibiting mTORC1 and may inadvertently inhibit mTORC2, leading to unintended consequences like Akt activation blockage.
Innovation Solution
Development of compounds that selectively inhibit either mTORC1 or mTORC2, or have no selectivity difference between the two, providing more targeted mTOR inhibition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Rapamycin is used to inhibit mTOR, then mTORC1 inhibition is achieved, but mTORC2 is also inadvertently inhibited leading to Akt activation blockage
Solution Approach 1:
The patent applies segmentation by designing compounds that selectively target either mTORC1 or mTORC2 based on the specific therapeutic need. The chemical structures are optimized to bind preferentially to one complex over the other, dividing the inhibition function into separate selective agents rather than using a single compound that affects both complexes
Solution Approach 2:
The patent employs local quality by modifying specific regions of the rapamycin analog structures (such as the C40, C28, or C-32 positions) to alter binding specificity. These localized structural changes enable the compounds to interact differently with mTORC1 versus mTORC2, achieving selective inhibition while maintaining the core macrocyclic lactone framework
2Measurement precision
If selective mTORC1 inhibitors are used, then S6K and S6 phosphorylation are strongly inhibited, but 4E-BP1 phosphorylation is only partially inhibited
Solution Approach 1:
The patent applies parameter changes by systematically varying chemical parameters of the rapamycin analogs, including substituent groups at different positions, ring size modifications, and stereochemical configurations. These parameter adjustments fine-tune the binding affinity and selectivity to achieve more complete inhibition of all mTORC1 substrates including 4E-BP1
3Reliability
If ATP-site mTOR inhibitors are used, then broader substrate phosphorylation is inhibited, but mTORC2 inhibition occurs leading to Akt activation blockage
Solution Approach 1:
The patent employs the intermediary principle by using the FRB domain as a mediator to achieve selective mTORC1 inhibition. The compounds bind to the FRB domain in complex with FKBP12, which acts as an intermediary that directs inhibition specifically to mTORC1 without affecting mTORC2, thus avoiding Akt activation blockage while maintaining broad substrate coverage
Data Source
AI summary
The present disclosure relates to mTOR inhibitors. Specifically, the embodiments are directed to compounds and compositions inhibiting mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.