CFTR Modulators Correcting F508del Protein Folding
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation in the CFTR gene, are inadequate in effectively addressing the severe forms of the disease, as they fail to adequately correct protein folding and trafficking, leading to insufficient anion and fluid transport in respiratory and digestive tissues.
Innovation Solution
Development of novel compounds, including those represented by Formulas I and II, which act as CFTR correctors to facilitate protein trafficking and enhance channel activity, potentially used in combination with existing CFTR modulators like tezacaftor, lumacaftor, ivacaftor, and deutivacaftor to improve ion transport and reduce disease severity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CFTR modulators are used to treat F508del mutation, then some anion transport function is restored, but protein folding and trafficking are not adequately corrected
Solution Approach 1:
The patent segments the CFTR modulator treatment into two distinct functional components: correctors that specifically address protein folding and trafficking defects, and potentiators that enhance channel activity. This segmentation allows each component to optimize its specific function without compromise, resolving the contradiction between partial transport restoration and inadequate folding correction.
Solution Approach 2:
The patent employs composite therapeutic strategies by combining multiple CFTR modulators with different mechanisms of action (correctors and potentiators) into combination therapies. This composite approach synergistically addresses both the folding/trafficking defects and the channel activity deficits, achieving comprehensive correction that neither single agent can accomplish alone.
2Quantity of substance
If F508del mutant CFTR protein is produced, then CFTR channels are present in the membrane, but the number of functional channels is far less than wild-type
Solution Approach 1:
The patent applies preliminary action by using corrector compounds that act upstream in the protein processing pathway to prevent the folding and trafficking defects before they occur. By intervening early in the protein maturation process, the correctors ensure that CFTR channels are properly folded and trafficked to the membrane in functional quantities, rather than attempting to rescue defective proteins after they have already accumulated errors.
Solution Approach 2:
The patent utilizes parameter changes by modifying the biophysical properties of the CFTR protein through small molecule binding. The correctors and potentiators alter key parameters such as protein folding stability, trafficking efficiency, and channel gating characteristics, transforming the defective F508del protein into a functional channel with wild-type-like performance.
3Quantity of substance
If F508del mutation occurs, then CFTR protein is produced, but defective channel gating results in reduced anion and fluid transport
Solution Approach 1:
The patent introduces small molecule compounds as intermediaries that bind to the CFTR protein and mediate the transmission of corrective effects. These intermediary molecules act as molecular chaperones and gating facilitators, bridging the gap between the defective F508del protein structure and the desired functional outcome, enabling proper channel gating and restoring anion transport productivity.
Data Source
AI summary
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the structure: (I), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, combination therapies, and processes and intermediates for making such modulators.