CFTR Modulator Combination for F508del Trafficking and Function
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation, are inadequate in effectively increasing CFTR protein function and stability at the cell surface, leading to severe respiratory and digestive issues, and there is a need for more effective CFTR modulating compounds.
Innovation Solution
The use of (14S)-8-[3-(2-{Dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 1,14.0 5,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I) and its pharmaceutically acceptable salts, along with other CFTR modulating agents like (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II) and N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound III), to correct and potentiate CFTR protein trafficking and function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CFTR modulating treatments are used for F508del mutation, then some CFTR protein function is restored, but the effectiveness in increasing CFTR protein function and stability at the cell surface is inadequate
Solution Approach 1:
The patent combines multiple CFTR modulating agents (Compound I as a corrector, and Compound II or III as potentiators) into a single therapeutic regimen. This combination approach merges the effects of trafficking correction with channel potentiation, achieving synergistic improvement in CFTR protein function and stability at the cell surface that exceeds the effect of single agents alone.
Solution Approach 2:
The invention uses a composite therapeutic approach by formulating Compound I in combination with other CFTR modulating agents. This composite therapy leverages the complementary mechanisms of different compounds to achieve enhanced and more reliable CFTR protein function compared to monotherapy.
2Ease of operation
If F508del mutation is present, then CFTR protein folding is impaired and trafficking to plasma membrane is blocked, but the mutant protein still retains some channel function
Solution Approach 1:
The patent applies preliminary action by using Compound I to correct CFTR protein folding and facilitate trafficking to the plasma membrane before the protein can exert its channel function. This pre-processing of the mutant protein ensures proper localization and stability, enabling the retained channel function to be effectively utilized at the cell surface.
Solution Approach 2:
Compound I acts as an intermediary that mediates between the defective F508del mutant CFTR protein and the cellular trafficking machinery. It facilitates the interaction between the misfolded protein and the quality control systems, enabling the protein to escape ER retention and reach the plasma membrane where it can function.
3Object-affected harmful factors
If anion transport is reduced due to defective CFTR, then mucus accumulation and microbial infections occur, but increasing CFTR function could potentially cause over-correction
Solution Approach 1:
The patent applies partial action by using CFTR modulating compounds that restore a portion of normal CFTR function rather than attempting to achieve complete wild-type levels. This partial restoration is sufficient to reduce mucus accumulation and infections while maintaining balance in ion and fluid transport, avoiding the risks of over-correction.
Data Source
AI summary
This application describes methods of treating cystic fibrosis or a CFTR mediated disease comprising administering Compound I or a pharmaceutically acceptable salt thereof. The application also describes pharmaceutical compositions comprising Compound I or a pharmaceutically acceptable salt thereof and optionally comprising one or more additional CFTR modulating agents.