CFTR Modulators Correcting F508del Protein Folding

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Solution Overview

Problem

Current treatments for cystic fibrosis, particularly those targeting the CFTR protein, face challenges in effectively addressing the F508del mutation, which leads to defective protein folding, trafficking, and ion transport imbalances, resulting in severe respiratory and gastrointestinal issues.

Innovation Solution

Development of novel compounds, including those with silicon, boron, or germanium substitutions, and their pharmaceutically acceptable salts and deuterated derivatives, which act as CFTR modulators to correct protein trafficking and enhance ion transport by replacing specific carbon atoms and modifying methyl and methylene groups, thereby addressing the defective trafficking and gating issues of the F508del mutation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CFTR treatments are used, then some anion transport function is maintained, but the F508del mutation causes defective protein folding and trafficking, resulting in insufficient CFTR channels at the cell surface

Engineering Contradiction:

ImproveCFTR channel functionVSAvoidnumber of CFTR channels at cell surface

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The compound acts on CFTR protein during its folding and trafficking process before it reaches the cell surface, correcting the F508del mutation defects in advance and enabling proper channel localization and function

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The compound changes the physical-chemical parameters of the CFTR protein folding process, stabilizing the correct conformation and improving trafficking efficiency to increase the number of functional channels at the cell surface

Inventive Principle:

Principle #35Parameter changes

2Productivity

If the F508del mutation is present, then protein synthesis occurs, but the mutant protein cannot exit the endoplasmic reticulum and traffic to the plasma membrane effectively

Engineering Contradiction:

Improveprotein synthesis rateVSAvoidprotein trafficking efficiency

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The compound acts as an intermediary molecule that facilitates the interaction between CFTR protein and the cellular trafficking machinery, enabling the mutant protein to successfully navigate from the endoplasmic reticulum to the plasma membrane

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If CFTR channels are present at the membrane, then anion transport occurs, but the F508del mutation results in defective channel gating and reduced transport function

Engineering Contradiction:

ImproveCFTR channels at membraneVSAvoidchannel gating function

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The compound prepares the CFTR channel gating mechanism in advance by binding to and stabilizing the correct conformational states, ensuring that when channels reach the membrane, they are capable of proper opening and closing function

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS11414439B2Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator

Publication Date: 2022.08.16 VERTEX PHARMACEUTICALS INC

AI summary

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis by administering such modulators and pharmaceutical compositions, and processes for making such modulators.