Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel

Nicoletta Pedemonte, Fabio Bertozzi, Emanuela Caci, Federico Sorana, Paolo Di Fruscia, Valeria Tomati, Loretta Ferrera, Alejandra Rodríguez-Gimeno, Francesco Berti, Emanuela Pesce, Elvira Sondo, Ambra Gianotti, Paolo Scudieri, Tiziano Bandiera, Luis J V Galietta

Research output: Contribution to journalArticlepeer-review

Abstract

F508del, the most frequent mutation causing cystic fibrosis (CF), results in mistrafficking and premature degradation of the CFTR chloride channel. Small molecules named correctors may rescue F508del-CFTR and therefore represent promising drugs to target the basic defect in CF. We screened a carefully designed chemical library to find F508del-CFTR correctors. The initial active compound resulting from the primary screening underwent extensive chemical optimization. The final compound, ARN23765, showed an extremely high potency in bronchial epithelial cells from F508del homozygous patients, with an EC50 of 38 picomolar, which is more than 5000-fold lower compared to presently available corrector drugs. ARN23765 also showed high efficacy, synergy with other types of correctors, and compatibility with chronic VX-770 potentiator. Besides being a promising drug, particularly suited for drug combinations, ARN23765 represents a high-affinity probe for CFTR structure-function studies.

Original languageEnglish
Pages (from-to)eaay9669
JournalScience advances
Volume6
Issue number8
DOIs
Publication statusPublished - Feb 2020

Keywords

  • Bronchi/pathology
  • Cell Line
  • Cystic Fibrosis Transmembrane Conductance Regulator/chemistry
  • Epithelial Cells/metabolism
  • High-Throughput Screening Assays
  • Humans
  • Mutant Proteins/metabolism
  • Pharmaceutical Preparations/metabolism

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