CFTR Modulators for Mutant Protein Folding and Trafficking

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Solution Overview

Problem

There is a need for compounds and methods to increase cystic fibrosis transmembrane conductance regulator (CFTR) activity and treat CFTR-related diseases, particularly cystic fibrosis, where mutations like ΔF508 lead to protein misfolding and defective trafficking, resulting in impaired lung function and other organ dysfunctions.

Innovation Solution

Disclosed are compounds represented by Formulas (Ia) and (Ib), or their pharmaceutically acceptable salts, prodrugs, or solvates, which can enhance CFTR activity in human bronchial epithelial cells, specifically designed to increase the activity of mutant CFTR proteins such as ΔF508, by administering effective amounts of these compounds to subjects in need.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If compounds are designed to increase CFTR activity in mutant proteins, then CFTR function is improved, but protein misfolding and defective trafficking persist

Engineering Contradiction:

ImproveCFTR functionVSAvoidprotein folding

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The compounds act on CFTR proteins during their folding and trafficking process in the endoplasmic reticulum, before the proteins reach their final destination. By intervening early in the protein lifecycle, the compounds can correct misfolding issues and improve trafficking efficiency, thereby resolving the contradiction between improving CFTR function and addressing protein folding defects

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The compounds modify the physical or chemical parameters of the CFTR protein environment, such as stabilizing the protein structure or altering cellular conditions, to enable proper folding and trafficking of mutant CFTR proteins. This parameter modification allows the proteins to achieve correct conformation and reach functional locations, simultaneously improving both folding accuracy and CFTR activity

Inventive Principle:

Principle #35Parameter changes

2Productivity

If CFTR activity is increased through compound treatment, then lung function improves, but the underlying mutation effects remain

Engineering Contradiction:

Improvelung functionVSAvoidmutation effects

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

The compounds convert the harmful effects of the CFTR mutation into beneficial outcomes by targeting the mutant proteins and enhancing their residual activity. Instead of attempting to eliminate the mutation, the compounds work with the mutant proteins' existing structure to amplify their functional output, thereby improving lung function while accepting the persistent presence of the mutation

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The compounds serve as intermediary agents between the mutant CFTR proteins and their functional requirements. By binding to the mutant proteins and facilitating their proper folding, stability, and trafficking, the compounds mediate the interaction between defective proteins and cellular machinery, enabling improved CFTR activity without altering the underlying genetic mutation

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS10017503B2Compounds, compositions, and methods for increasing CFTR activity

Publication Date: 2018.07.10 PROTEOSTASIS THERAPEUTICS INC

AI summary

The disclosure encompasses compounds having e.g., Formula (Ia) or (Ib), compositions thereof, and methods of modulating CFTR activity. The disclosure also encompasses methods of treating a condition associated with CFTR activity or condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a compound of Formula (I) or (Ib).