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

Science Advances
Nicoletta PedemonteLuis J V Galietta

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.

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Citations

Aug 21, 2020·JCI Insight·Génesis VegaCarlos A Flores
Mar 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Virginia SpanòPaola Barraja
Apr 8, 2021·Expert Opinion on Drug Discovery·Miquéias Lopes-PachecoGuido Veit
Jun 3, 2021·International Journal of Molecular Sciences·Valeria CapurroNicoletta Pedemonte
Jul 31, 2021·Journal of Experimental Pharmacology·Madalena C PintoMiquéias Lopes-Pacheco
Oct 14, 2021·American Journal of Physiology. Cell Physiology·Alan S Verkman, Luis J V Galietta

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Methods Mentioned

BETA
glycosylation
column chromatography
electrophoresis

Software Mentioned

ImageJ
Vertex
Symdeko

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