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PP-2, a src-kinase inhibitor, is a potential corrector for F508del-CFTR in cystic fibrosis

Yunguan Wang, Kavisha Arora, Fanmuyi Yang, Woong-Hee Shin, Jing Chen, Daisuke Kihara, Anjaparavanda P. Naren, Anil G. Jegga
doi: https://doi.org/10.1101/288324
Yunguan Wang
1Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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Kavisha Arora
2Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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Fanmuyi Yang
2Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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Woong-Hee Shin
3Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
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Jing Chen
1Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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Daisuke Kihara
3Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
4Department of Computer Science, Purdue University, West Lafayette, Indiana, USA
5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Anjaparavanda P. Naren
2Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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  • For correspondence: anil.jegga@cchmc.org anaren@cchmc.org
Anil G. Jegga
1Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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  • For correspondence: anil.jegga@cchmc.org anaren@cchmc.org
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Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The most common mutation in CF, an in-frame deletion of phenylalanine 508, leads to a trafficking defect and endoplasmic reticulum retention of the protein where it becomes targeted for degradation. Successful clinical deployments of ivacaftor and ivacaftor/lumacaftor combination have been an exciting translational development in treating CF. However, their therapeutic effects are variable between subjects and remain insufficient. We used the Library of Integrated Network-based Cellular Signatures (LINCS) database as our chemical pool to screen for candidates. For in silico screening, we integrated connectivity mapping and CF systems biology to identify candidate therapeutic compounds for CF. Following in silico screening, we validated our candidate compounds with (i) an enteroid-based compound screening assay using CF (ΔF508/ΔF508-CFTR) patient-derived enteroids, (ii) short-circuit current analysis using polarized CF primary human airway epithelial cells and (iii) Western blots to measure F508-del-CFTR protein maturation. We identified 184 candidate compounds with in silico screening and tested 24 of them with enteroid-based forskolin-induced swelling (FIS) assay. The top hit compound was PP2, a known src-kinase inhibitor that induced swelling in enteroid comparable to known CF corrector (lumacaftor). Further validation with Western blot and short-circuit current analysis showed that PP-2 could correct mutant CFTR mis-folding and restore CFTR-mediated transmembrane current. We have identified PP2, a known src-kinase inhibitor, as a novel corrector of ΔF508-CFTR. Based on our studies and previous reports, src kinase inhibition may represent a novel paradigm of multi-action therapeutics – corrector, anti-inflammatory, and anti-infective – in CF.

  • Abbreviations

    CF
    Cystic fibrosis
    CFTR
    CF transmembrane conductance regulator
    LINCS
    Library of Integrated Network-based Cellular Signatures
    FIS
    Forskolin-induced-swelling
    CFRE
    CF rectal epithelia
    Isc
    short circuit currents
    DEG
    differentially expressed gene
    GSEA
    gene set enrichment analysis
    SEA
    singular enrichment analysis
    PsA
    Pseudomonas aeruginosa
    PP2
    1-tert-Butyl-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  • Copyright 
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    Posted March 24, 2018.
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    PP-2, a src-kinase inhibitor, is a potential corrector for F508del-CFTR in cystic fibrosis
    Yunguan Wang, Kavisha Arora, Fanmuyi Yang, Woong-Hee Shin, Jing Chen, Daisuke Kihara, Anjaparavanda P. Naren, Anil G. Jegga
    bioRxiv 288324; doi: https://doi.org/10.1101/288324
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    PP-2, a src-kinase inhibitor, is a potential corrector for F508del-CFTR in cystic fibrosis
    Yunguan Wang, Kavisha Arora, Fanmuyi Yang, Woong-Hee Shin, Jing Chen, Daisuke Kihara, Anjaparavanda P. Naren, Anil G. Jegga
    bioRxiv 288324; doi: https://doi.org/10.1101/288324

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