Identification of Synergistic Combinations of F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Lin, Stephen; Sui, Jinliang; Cotard, Shakira; Fung, Brenda P.; Andersen, Jennifer; Zhu, Ping; Messadi, Najib El; Lehár, Joseph; Lee, Margaret; Staunton, Jane

doi:10.1089/adt.2010.0313

Cited by 21 publications

(16 citation statements)

References 57 publications

(69 reference statements)

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“…It remains to be determined whether the limited efficacy of available correctors can be overcome with improved understanding of the folding pathway and molecular partners of F508del-CFTR. As a more immediate approach to enhance efficacy, it has been shown that combinations of F508del correctors can have additive or even synergistic effects (Bridges 2010; Lin et al 2010), supporting the idea that more than one cellular mechanism is relevant to the cellular recognition and degradation of F508del-CFTR. The use of CFTR potentiators in combination with CFTR correctors represents another option to overcome deficits in efficient functional rescue for the protein.…”

Section: Correctorsmentioning

confidence: 95%

Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators

Rowe

Verkman

2013

Cold Spring Harbor Perspectives in Medicine

139

121

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Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing.

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Section: Correctorsmentioning

confidence: 95%

Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators

Rowe

Verkman

2013

Cold Spring Harbor Perspectives in Medicine

139

121

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“…Hundreds of compounds classified as CFTR correctors have been identified in literature to date (Pedemonte et al, 2005; Van Goor et al, 2006; Carlile et al, 2007; Kalid et al, 2010; Lin et al, 2010; Van Goor et al, 2011). Most of these molecules are deemed unsuitable for clinical use namely due to low efficacy, cell type specificity, and/or toxicity profiles.…”

Section: Mechanism Of Action Of Existing Corrector Compoundsmentioning

confidence: 99%

“…It is interesting to note that previous corrector screens have used chemical libraries of 2,000–164,000 compounds, and typically the hit rate is ∼0.01–0.03% (Lin et al, 2010). This low yield suggests that larger libraries would be more successful.…”

Section: Drug Discoverymentioning

confidence: 99%

“…Lin et al (2010) used a library containing >3,000 FDA-approved drugs to search for small molecule correctors and potentiators in cell-based assays, and ∼40 chemicals with F508del-CFTR corrector activity were identified. Their choice to screen previously approved drugs is advantageous, since it would streamline application from bench to bedside, saving many years it would normally take to become approved for human indications.…”

Section: Drug Discoverymentioning

confidence: 99%

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Functional Rescue of F508del-CFTR Using Small Molecule Correctors

Molinski¹,

Eckford²,

Pasyk³

et al. 2012

Front. Pharmacol.

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High-throughput screens for small molecules that are effective in “correcting” the functional expression of F508del-CFTR have yielded several promising hits. Two such compounds are currently in clinical trial. Despite this success, it is clear that further advances will be required in order to restore 50% or greater of wild-type CFTR function to the airways of patients harboring the F508del-CFTR protein. Progress will be enhanced by our better understanding of the molecular and cellular defects caused by the F508del mutation, present in 90% of CF patients. The goal of this chapter is to review the current understanding of defects caused by F508del in the CFTR protein and in CFTR-mediated interactions important for its biosynthesis, trafficking, channel function, and stability at the cell surface. Finally, we will discuss the gaps in our knowledge regarding the mechanism of action of existing correctors, the unmet need to discover compounds which restore proper CFTR structure and function in CF affected tissues and new strategies for therapy development.

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“…Even after corrector treatment, F508del-CFTR has <15% the activity of CFTR wild-type (WT), and the corrector efficacy may vary depending on the cell type examined (13)(14)(15)(16). More robust rescue can be achieved by using a combination of correctors, which enhances rescue to levels greater than individual compound actions (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Rescue of the Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Detected by Use of a Novel Fluorescence Platform

Holleran

Glover

Peters

et al. 2012

Mol Med

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Numerous human diseases arise because of defects in protein folding, leading to their degradation in the endoplasmic reticulum. Among them is cystic fibrosis (CF), caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR ), an epithelial anion channel. The most common mutation, F508del, disrupts CFTR folding, which blocks its trafficking to the plasma membrane. We developed a fluorescence detection platform using fluorogen-activating proteins (FAPs) to directly detect FAP-CFTR trafficking to the cell surface using a cell-impermeant probe. By using this approach, we determined the efficacy of new corrector compounds, both alone and in combination, to rescue F508del-CFTR to the plasma membrane. Combinations of correctors produced additive or synergistic effects, improving the density of mutant CFTR at the cell surface up to ninefold over a single-compound treatment. The results correlated closely with assays of stimulated anion transport performed in polarized human bronchial epithelia that endogenously express F508del-CFTR. These findings indicate that the FAP-tagged constructs faithfully report mutant CFTR correction activity and that this approach should be useful as a screening assay in diseases that impair protein trafficking to the cell surface.

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Identification of Synergistic Combinations of F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Cited by 21 publications

References 57 publications

Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators

Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators

Functional Rescue of F508del-CFTR Using Small Molecule Correctors

Pharmacological Rescue of the Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Detected by Use of a Novel Fluorescence Platform

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