CFTR Modulator Combination Therapy for F508del Trafficking
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Solution Overview
Problem
Current treatments for cystic fibrosis (CF) are inadequate, particularly for patients with the F508del mutation, as they fail to effectively correct the defective trafficking and channel gating of the CFTR protein, leading to persistent ion and fluid transport imbalances and associated respiratory and gastrointestinal issues.
Innovation Solution
Development of a compound of Formula I, or its pharmaceutically acceptable salt, which modulates CFTR function by correcting trafficking defects and enhancing channel activity, thereby improving ion transport across epithelial cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CFTR modulators are used, then some CFTR function is restored, but the amount of functional CFTR protein at the cell surface remains insufficient
Solution Approach 1:
The patent combines multiple CFTR modulator compounds in specific combinations (e.g., Compound A + Compound B, or Compound A + Compound C) to achieve synergistic effects. This merging of multiple agents addresses the limitation of single modulators by simultaneously targeting different aspects of CFTR function: one compound promotes protein folding and trafficking to the cell surface, while another enhances channel gating activity, thereby increasing both the amount and functionality of CFTR protein.
Solution Approach 2:
The patent optimizes dosing parameters including the ratio of compounds in combination therapy (e.g., 1:1, 1:2, or 2:1 ratios), administration timing, and dosage levels to maximize CFTR protein expression and channel activity. By adjusting these parameters, the treatment achieves sufficient quantities of functional CFTR at the cell surface that single-agent therapies cannot achieve alone.
2Reliability
If higher doses of single CFTR modulators are administered, then CFTR activity increases, but side effects and toxicity increase
Solution Approach 1:
The patent employs combination therapy where two or more CFTR modulators are administered together at lower individual doses than would be required for monotherapy. This approach distributes the therapeutic effect across multiple agents, achieving sufficient CFTR activity while reducing the toxic burden on any single compound and thereby minimizing side effects.
Solution Approach 2:
The patent uses one CFTR modulator as a trafficking corrector that enables proper protein folding and cell surface expression, which then serves as a foundation for the second modulator (a potentiator) to enhance channel gating. This intermediary role of the first compound allows the second compound to work more effectively at lower doses, reducing overall toxicity.
3Adaptability or versatility
If F508del mutant CFTR protein is produced, then the protein fails to fold correctly and traffic to the plasma membrane, but the mutation is present in 70% of CF cases
Solution Approach 1:
The patent converts the harmful effect of F508del mutation (impaired protein folding and trafficking) into a treatable condition by using CFTR corrector compounds that specifically bind to the misfolded mutant protein and stabilize its structure. This allows the previously non-functional protein to undergo correct folding, escape ER quality control, and traffic to the plasma membrane where it can perform its physiological function.
Solution Approach 2:
The patent employs CFTR corrector compounds as molecular chaperones that act as intermediaries between the misfolded F508del mutant protein and the cellular protein quality control system. These correctors bind to the mutant protein, prevent its degradation by proteasomes, and facilitate its proper folding and trafficking to the cell surface, thereby rescuing the protein from the harmful effects of the mutation.
Data Source
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AI summary
The present disclosure features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R1, R2, W, X, Z, n, p, and Rings A and B are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present disclosure also features pharmaceutical compositions, method of treating, and kits thereof.