Intermittent RAS(ON) Inhibitor Dosing to Limit Wild-Type RAS Toxicity
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Solution Overview
Problem
Current treatments for RAS protein-related diseases, such as cancer, are limited by severe toxicities due to the inhibition of wild-type RAS, which is essential for normal cellular functions, and there is a need for effective and enhanced treatment methods.
Innovation Solution
Administering RAS(ON) multi-selective inhibitors on an intermittent dosing regimen to minimize toxicity to normal tissues by allowing RAS pathway reactivation and using compounds with higher binding affinity to cyclophilin A (low KD1 value) to form a tri-complex structure inhibiting both mutant and wild-type RAS variants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If continuous dosing of RAS(ON) multi-selective inhibitors is used, then therapeutic efficacy is maintained, but toxicities to normal tissues increase
Solution Approach 1:
The patent applies periodic action by implementing intermittent dosing regimens where the RAS(ON) multi-selective inhibitor is administered for a predetermined number of days followed by a drug-free interval. This periodic administration allows the RAS pathway to reactivate during off-periods, reducing cumulative toxicity to normal tissues while maintaining therapeutic pressure on tumors during on-periods. The dosing regimen may be repeated for multiple cycles to sustain anti-tumor activity.
2Reliability
If higher binding affinity compounds (low KD1 value) are used, then inhibition of mutant and wild-type RAS is enhanced, but toxicities to normal tissues increase
Solution Approach 1:
The patent applies parameter changes by selecting RAS(ON) multi-selective inhibitors with specific binding affinity parameters (KD1 values) and combining this with changes in dosing parameters (intermittent vs continuous, dose intensity). The intermittent dosing regimen modifies the temporal parameter of drug exposure, allowing the system to benefit from high binding affinity compounds while mitigating their toxic effects through reduced cumulative exposure time.
3Object-affected harmful factors
If intermittent dosing regimen is used, then toxicities to normal tissues are reduced, but dosing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the treatment course into discrete segments: an on-period consisting of multiple consecutive days of dosing followed by an off-period with no dosing. This segmentation of the dosing timeline creates a manageable pattern that reduces overall toxicity while maintaining therapeutic efficacy. The segmentation approach transforms complex continuous dosing into simpler cyclic on-off patterns that are easier to administer and monitor.
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 reduces dose-limiting toxicities while maintaining therapeutic efficacy by intermittently administering RAS(ON) multi-selective inhibitors, ensuring prolonged RAS pathway inhibition in tumors while minimizing effects on normal tissues.
Implementation Method 1
The RAS(ON) multi-selective inhibitor binds to chaperone protein cyclophilin A (CypA) to form a binary complex, that then inhibits the RAS proteins (e.g., mutant and wild-type RAS variants) by forming a tri-complex structure
Implementation Method 2
activating mutations at codon 12 in RAS proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of RAS mutant proteins to the 'on' (GTP-bound) state
Data Source
AI summary
Disclosed are RAS(ON) multi-selective inhibitor compositions and methods of treating RAS protein-related diseases or disorders using an intermittent dosing regimen. RAS(ON) multi-selective inhibitors having tight binding to cyclophilin A (CypA) result in high exposure levels, prolonged tissue retention, and/or slow clearance rates, thereby increasing the risk of inhibition of wild-type RAS in normal tissues. Accordingly, provided herein are methods for the safe and effective dosing of low KD1 RAS(ON) multi-selective inhibitors using an intermittent dosing regimen. Also provided are methods of selecting or identifying such RAS(ON) multi-selective inhibitors suitable for intermittent administration.