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

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 EC 50 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.

Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta

“…DMSO was used as control incubation. For each of these incubations, CFTR rescue was verified as described previously (24). After pelleting and lipid extraction, an extensive lipid profiling by high-resolution LC-MS was performed on these samples.…”

“…Although VX-809 is not part of the newly developed combination drugs, we decided to test it because of the reported negative effect on CFTR half-life at the plasma membrane following chronic coadministration of VX-770 and VX-809 (21,22). CFTR rescue was verified as recently described (24).…”

“…All the samples, including procedure blanks, were extracted following this protocol. The whole sample set, consisting of a total of 64 samples, was then randomized, split into 4 batches, and analyzed by high-resolution LC-MS, using the methods already optimized by our group for untargeted lipidomics ( 24 – 27 ). For every batch, a QC sample was prepared by pooling together 5 μL of all the samples of that batch, including blanks and procedure blanks.…”

Choice of Differentiation Media Significantly Impacts Cell Lineage and Response to CFTR Modulators in Fully Differentiated Primary Cultures of Cystic Fibrosis Human Airway Epithelial Cells

“…Nonetheless, if F508del-CFTR traffics to the cell surface via the unconventional pathway (see above), then this could provide an explanation for the presence of SLC26A9 as well. Overall, these findings have important implications when in vitro cell cultures are used for drug discovery [ 93 ], particularly in the case of CFTR modulators [ 94 ] and more recently for personalized therapy, especially in the case of very rare CFTR mutations [ 95 ], in which choosing the right cell growth method could lead to findings that may not be replicated by a different growth protocol.…”

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

“…Although patients with CF have found therapies in molecules that help correct mutant CFTR malfunctions (64,65), and new such molecules are being discovered (66), almost 10% of patients with CF are still left with no such treatment. The potential use of KCa3.1 inhibitors corresponds with what has been called a "mutation-agnostic" treatment that might be used specially in patients with CF that are not eligible for the new available therapies, and it also seems suitable for easing other muco-obstructive diseases affecting humans.…”