Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508‐CFTR for cystic fibrosis

Rachel A. Hodos; Matthew D. Strub; Shyam Ramachandran; Ella A. Meleshkevitch; Dmitri Y. Boudko; Robert J. Bridges; Joel T. Dudley; Paul B. McCray

doi:10.1002/psp4.12626

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Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508‐CFTR for cystic fibrosis

Journal article

Open access

Peer reviewed

Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508‐CFTR for cystic fibrosis

Rachel A. Hodos, Matthew D. Strub, Shyam Ramachandran, Ella A. Meleshkevitch, Dmitri Y. Boudko, Robert J. Bridges, Joel T. Dudley and Paul B. McCray

CPT: pharmacometrics and systems pharmacology, Vol.10(5), pp.500-510

05/2021

DOI: 10.1002/psp4.12626

PMCID: PMC8129714

PMID: 33934548

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Abstract

Rare diseases affect 10% of the first‐world population, yet over 95% lack even a single pharmaceutical treatment. In the present age of information, we need ways to leverage our vast data and knowledge to streamline therapeutic development and lessen this gap. Here, we develop and implement an innovative informatic approach to identify therapeutic molecules, using the Connectivity Map and LINCS L1000 databases and disease‐associated transcriptional signatures and pathways. We apply this to cystic fibrosis (CF), the most common genetic disease in people of northern European ancestry leading to chronic lung disease and reduced lifespan. We selected and tested 120 small molecules in a CF cell line, finding 8 with activity, and confirmed 3 in primary CF airway epithelia. Although chemically diverse, the transcriptional profiles of the hits suggest a common mechanism associated with the unfolded protein response and/or TNFα signaling. This study highlights the power of informatics to help identify new therapies and reveal mechanistic insights while moving beyond target‐centric drug discovery.

Details

Title: Subtitle: Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508‐CFTR for cystic fibrosis
Creators: Rachel A. Hodos - Courant Institute of Mathematical Sciences
Matthew D. Strub - University of Iowa
Shyam Ramachandran - Editas Medicine (United States)
Ella A. Meleshkevitch - Rosalind Franklin University of Medicine and Science
Dmitri Y. Boudko - Rosalind Franklin University of Medicine and Science
Robert J. Bridges - Rosalind Franklin University of Medicine and Science
Joel T. Dudley - Icahn School of Medicine at Mount Sinai
Paul B. McCray - University of Iowa
Resource Type: Journal article
Publication Details: CPT: pharmacometrics and systems pharmacology, Vol.10(5), pp.500-510
DOI: 10.1002/psp4.12626
PMID: 33934548
PMCID: PMC8129714
NLM abbreviation: CPT Pharmacometrics Syst Pharmacol
ISSN: 2163-8306
eISSN: 2163-8306
Number of pages: 11
Grant note: National Institutes of Health (RO1 HL118000; P01 HL51670; P01 HL091842; T32GM008629) Center for Gene Therapy of Cystic Fibrosis (P30 DK54759) Roy J. Carver Charitable Trust Cystic Fibrosis Foundation
Language: English
Date published: 05/2021
Academic Unit: Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
Record Identifier: 9984297320802771

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