ArticleMolecular & cellular proteomics : MCP2012
Use of kinase inhibitors to correct ΔF508-CFTR function.
Article in Molecular & cellular proteomics : MCP, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Recent developments in cystic fibrosis drug discovery: where are we today?Expert opinion on drug discovery · 2025Review
- Comprehensive Profiling and Therapeutic Insights into Differentially Expressed Genes in Hepatocellular Carcinoma.Cancers · 2023Article
- A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma.APL bioengineering · 2023Article
- Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306.Journal of medicinal chemistry · 2022Article
- Targeting the EGFR-ERK axis using the compatible solute ectoine to stabilize CFTR mutant F508del.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives.Journal of medicinal chemistry · 2022Review
- Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network-based Cellular Signatures drug discovery platform.CPT: pharmacometrics & systems pharmacology · 2022Article
- Article
- Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.PLoS genetics · 2018Article
- Cystic fibrosis transmembrane conductance regulator-emerging regulator of cancer.Cellular and molecular life sciences : CMLS · 2018Review
- Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase.Developmental cell · 2018Article
- High-Content Surface and Total Expression siRNA Kinase Library Screen with VX-809 Treatment Reveals Kinase Targets that Enhance F508del-CFTR Rescue.Molecular pharmaceutics · 2018Article
- Peripheral Protein Quality Control as a Novel Drug Target for CFTR Stabilizer.Frontiers in pharmacology · 2018Review
- Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis.Scientific reports · 2017Article
- CFTR pharmacology.Cellular and molecular life sciences : CMLS · 2017Review
- Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants.Hepatology (Baltimore, Md.) · 2016Article
- Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis.Journal of innate immunity · 2016Review
- Article
- RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR.Molecular & cellular proteomics : MCP · 2015Article
- Enhancing the Potency of F508del Correction: A Multi-Layer Combinational Approach to Drug Discovery for Cystic Fibrosis.Journal of pharmacology & clinical toxicology · 2013Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The most common mutation in cystic fibrosis (CF) is a deletion of Phe at position 508 (ΔF508-CFTR). ΔF508-CFTR is a trafficking mutant that is retained in the ER, unable to reach the plasma membrane. To identify compounds and drugs that rescue this trafficking defect, we screened a kinase inhibitor library enriched for small molecules already in the clinic or in clinical trials for the treatment of cancer and inflammation, using our recently developed high-content screen technology (Trzcinska-Daneluti et al. Mol. Cell. Proteomics 8:780, 2009). The top hits of the screen were further validated by (1) biochemical analysis to demonstrate the presence of mature (Band C) ΔF508-CFTR, (2) flow cytometry to reveal the presence of ΔF508-CFTR at the cell surface, (3) short-circuit current (Isc) analysis in Ussing chambers to show restoration of function of the rescued ΔF508-CFTR in epithelial MDCK cells stably expressing this mutant (including EC(50) determinations), and importantly (4) Isc analysis of Human Bronchial Epithelial (HBE) cells harvested from homozygote ΔF508-CFTR transplant patients. Interestingly, several inhibitors of receptor Tyr kinases (RTKs), such as SU5402 and SU6668 (which target FGFRs, VEGFR, and PDGFR) exhibited strong rescue of ΔF508-CFTR, as did several inhibitors of the Ras/Raf/MEK/ERK or p38 pathways (e.g. (5Z)-7-oxozeaenol). Prominent rescue was also observed by inhibitors of GSK-3β (e.g. GSK-3β Inhibitor II and Kenpaullone). These results identify several kinase inhibitors that can rescue ΔF508-CFTR to various degrees, and suggest that use of compounds or drugs already in the clinic or in clinical trials for other diseases can expedite delivery of treatment for CF patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.