Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis

Plas, Steven E Van der; Kelgtermans, Hans; Mammoliti, Oscar; Menet, Christel J.; Tricarico, Giovanni; Blieck, Ann De; Joannesse, Caroline; Munck, Tom De; Lambin, Dominique; Cowart, Marlon; Dropsit, Sébastien; Martina, Sébastien L. X.; Gees, Maarten; Wesse, Anne-Sophie; Conrath, Katja; Andrews, Martin

doi:10.1021/acs.jmedchem.0c01796

Cited by 19 publications

(14 citation statements)

References 29 publications

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“…It works upon binding at the interface of the two CFTR’s MSDs [ 49 ]; however, ivacaftor-based treatment results in minor benefit to patients [ 48 ] with only 10% enhanced lung function [ 50 ]. Other potentiators have been identified and are now under preclinical characterization or in drug development pipeline [ 51 – 53 ], but some of them give off-targets effects [ 54 ]. Despite the current ivacaftor/lumacaftor combination therapy (Orkambi and more recently Trikafta from Vertex Pharmaceuticals) designed for CF patients with the genetic F508del mutation in homozygosity have a good efficacy [ 20 ], treatment of lung pathology in CF would take advantage from antimicrobial compounds with a repairing action of the lung epithelium in addition to a potentiation of CFTR activity.…”

Section: Discussionmentioning

confidence: 99%

Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides

Ferrera

Cappiello

Loffredo

et al. 2021

Cell. Mol. Life Sci.

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Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease. Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity. In this study, by means of electrophysiological techniques and computational studies we discovered their ability to increase the CFTR-controlled ion currents, by direct interaction with the F508del-CFTR mutant. Remarkably, this property was not explored previously with any AMPs or peptides in general. More interestingly, in contrast with clinically used CFTR modulators, Esc peptides would give particular benefit to CF patients by combining their capability to eradicate lung infections and to act as promoters of airway wound repair with their ability to ameliorate the activity of the channel with conductance defects. Overall, our findings not only highlighted Esc peptides as the first characterized AMPs with a novel property, that is the potentiator activity of CFTR, but also paved the avenue to investigate the functions of AMPs and/or other peptide molecules, for a new up-and-coming pharmacological approach to address CF lung disease.

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Section: Discussionmentioning

confidence: 99%

Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides

Ferrera

Cappiello

Loffredo

et al. 2021

Cell. Mol. Life Sci.

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“…These molecules were demonstrated to rescue mutant CFTR carrying G551D, G178R, R334W, S549N or F508del – the latter in combination with either VX-809 or ABBV-2222 – in both cell lines and CF HBE. 73 , 92 , 93 Patch-clamp functional studies showed that ABBV-974 and GLPG-2451 reduce the closed time and increase the open time of CFTR channels by a similar mechanism to that of VX-770, as no additive effects were observed when these molecules were tested together. 73 , 92 , 93 ABBV-3067 is another potentiator developed by Abbvie that was demonstrated to rescue F508del-CFTR in combination with the corrector ABBV-2222, 74 and this combination is currently under clinical investigation (NCT03969888).…”

Section: Cftr Modulator Drugs and Personalized Medicinementioning

confidence: 99%

“… 73 , 92 , 93 Patch-clamp functional studies showed that ABBV-974 and GLPG-2451 reduce the closed time and increase the open time of CFTR channels by a similar mechanism to that of VX-770, as no additive effects were observed when these molecules were tested together. 73 , 92 , 93 ABBV-3067 is another potentiator developed by Abbvie that was demonstrated to rescue F508del-CFTR in combination with the corrector ABBV-2222, 74 and this combination is currently under clinical investigation (NCT03969888). Abbvie also has two other investigational potentiators that are being pre-clinically tested: AC2-2 and AP2.…”

Section: Cftr Modulator Drugs and Personalized Medicinementioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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“…6 Most recently, the addition of a second site CFTR corrector agent to a potentiator−corrector combination was shown to give improvement in lung function in both hetero-and homozygous F508del CF patients, leading to the 2019 US registration of the ivacaftor−tezacaftor−elexacaftor (Trikafta) fixed dose combination. 7 Further CFTR potentiator−corrector combinations are in development from AbbVie, with the clinical stage potentiators GLPG1837 2 8 and GLPG2451 3 9 (Figure 1) disclosed, and the broader field of CFTR potentiator discovery has also been recently reviewed. 10 Chronic obstructive pulmonary disease (COPD) is anticipated to shortly become the third leading cause of death globally.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

et al. 2021

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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7–33 to establish structure–activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.

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Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis

Cited by 19 publications

References 29 publications

Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides

Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

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