CFTR Modulators Correcting Protein Trafficking and Gating
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation, are inadequate in effectively addressing the severe forms of the disease due to impaired protein folding and trafficking of the CFTR protein, leading to reduced anion and fluid transport across epithelia.
Innovation Solution
Development of novel compounds, including those represented by Formula I, which are CFTR modulators that correct protein trafficking and enhance channel activity, potentially used in combination with existing CFTR potentiators and correctors like tezacaftor, lumacaftor, ivacaftor, and deutivacaftor, to improve ion transport and reduce disease severity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If F508del mutation occurs in CFTR, then protein folding is impaired and trafficking is blocked, but this leads to reduced number of functional channels in the membrane
Solution Approach 1:
Corrector compounds act as molecular intermediaries that bind to the misfolded CFTR protein and facilitate its proper folding and trafficking to the cell membrane. These compounds mediate between the defective mutant protein and the cellular quality control machinery, enabling the protein to escape ER retention and reach its functional destination.
Solution Approach 2:
The invention changes the biophysical parameters of the CFTR protein by introducing small molecule compounds that alter the protein's folding landscape, stability, and conformational dynamics. This enables the mutant protein to adopt functional conformations that would otherwise be inaccessible, improving both trafficking and channel gating.
2Reliability
If F508del mutation occurs in CFTR, then channel gating is defective, but this leads to reduced anion and fluid transport across epithelia
Solution Approach 1:
Potentiator compounds serve as molecular intermediaries that bind to the CFTR channel and enhance its gating efficiency. These compounds mediate between the defective channel protein and the ion transport function, increasing the probability of channel opening and improving anion conductance without requiring changes to the primary protein sequence.
Solution Approach 2:
Potentiator compounds change the gating parameters of the CFTR channel by stabilizing the open state, increasing channel conductance, or reducing the energy barrier for channel opening. This directly improves the productivity of anion transport by modifying the kinetic and thermodynamic parameters of channel function.
3Reliability
If current CFTR modulators are used, then some improvement in protein function is achieved, but treatment is inadequate for severe forms of the disease
Solution Approach 1:
The invention combines corrector and potentiator compounds into integrated therapeutic regimens that simultaneously address both trafficking and gating defects. This merged approach delivers synergistic effects where the corrector restores protein localization while the potentiator enhances channel function, achieving greater therapeutic benefit than either compound alone.
Solution Approach 2:
The therapeutic strategy employs composite pharmacological formulations containing multiple CFTR modulating compounds with complementary mechanisms of action. This composite approach creates a multi-faceted therapeutic effect that addresses multiple aspects of CFTR dysfunction, thereby reducing harmful effects more effectively than single-agent therapies.
Data Source
AI summary
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treatment of mediated diseases, such as cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and therapies comprising such modulators, and processes and intermediates for making such modulators.