Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network-based Cellular Signatures drug discovery platform

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.

Automated summary

Cystic fibrosis is a lethal genetic disease caused by mutations in the CFTR gene, leading to misfolded proteins and degradation. Several strategies have been developed to partially correct CFTR function in vitro, but translating these interventions into therapies remains a challenge.