Journal article
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 and systems pharmacology, Vol.11(2), pp.240-251
02/01/2022
DOI: 10.1002/psp4.12751
PMCID: PMC8846631
PMID: 34877817
Abstract
Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The common Delta F508-CFTR mutation results in protein misfolding and proteasomal degradation. If Delta F508-CFTR trafficks to the cell surface, its anion channel function may be partially restored. Several in vitro strategies can partially correct Delta F508-CFTR trafficking and function, including low-temperature, small molecules, overexpression of miR-138, or knockdown of SIN3A. The challenge remains to translate such interventions into therapies and to understand their mechanisms. One approach for connecting such interventions to small molecule therapies that has previously succeeded for CF and other diseases is via mRNA expression profiling and iterative searches of small molecules with similar expression signatures. Here, we query the Library of Integrated Network-based Cellular Signatures using transcriptomic signatures from previously generated CF expression data, including RNAi- and low temperature-based rescue signatures. This LINCS in silico screen prioritized 135 small molecules that mimicked our rescue interventions based on their genomewide transcriptional perturbations. Functional screens of these small molecules identified eight compounds that partially restored Delta F508-CFTR function, as assessed by cAMP-activated chloride conductance. Of these, XL147 rescued Delta F508-CFTR function in primary CF airway epithelia, while also showing cooperativity when administered with C18. Improved CF corrector therapies are needed and this integrative drug prioritization approach offers a novel method to both identify small molecules that may rescue Delta F508-CFTR function and identify gene networks underlying such rescue.
Details
- Title: Subtitle
- Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network-based Cellular Signatures drug discovery platform
- Creators
- Matthew D. Strub - University of IowaShyam Ramachandran - University of IowaDmitri Y. Boudko - Rosalind Franklin University of Medicine and ScienceElla A. Meleshkevitch - Rosalind Franklin University of Medicine and ScienceAlejandro A. Pezzulo - University of IowaAravind Subramanian - Broad InstituteArthur Liberzon - Broad InstituteRobert J. Bridges - Rosalind Franklin University of Medicine and SciencePaul B. McCray - University of Iowa
- Resource Type
- Journal article
- Publication Details
- CPT: pharmacometrics and systems pharmacology, Vol.11(2), pp.240-251
- DOI
- 10.1002/psp4.12751
- PMID
- 34877817
- PMCID
- PMC8846631
- NLM abbreviation
- CPT Pharmacometrics Syst Pharmacol
- ISSN
- 2163-8306
- eISSN
- 2163-8306
- Publisher
- Wiley
- Number of pages
- 12
- Grant note
- P30 DK54759 / Center for Gene Thera of Cystic Fibrosis Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation Vitro Models and Cell Culture Core Roy J. Carver Charitable Trust RO1 HL118000; P01 HL51670; P01 HL091842 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 02/01/2022
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Internal Medicine
- Record Identifier
- 9984297427602771
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