Structural Analog of Sildenafil Identified as a Novel Corrector of the F508del-CFTR Trafficking Defect

Robert, Renaud; Carlile, Graeme W.; Pavel, Cătălin; Liu, Na; Anjos, Suzana M.; Liao, Jie; Luo, Yishan; Zhang, Donglei; Thomas, David Y.; Hanrahan, John W.

doi:10.1124/mol.107.040725

Cited by 109 publications

(98 citation statements)

References 40 publications

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“…Among them, small molecules called correctors are directed against class II mutations, including the most frequent mutation in CF patients, a deletion of F508 (ΔF508-CFTR) leading to improper folding, endoplasmic reticulum trapping and protein degradation [14,15]. Efficient CFTR maturation and delivery to the cell membrane has been reported after treatment with various corrector molecules, including corr-2b, corr-4a, VRT-325, MPB-07, KM1160, C18 and VX-809 [16][17][18][19][20][21][22][23][24][25]. However, to the best of our knowledge most high throughput screening assays to identify efficient corrector molecules are performed in the absence of infectious products.…”

Section: Introductionmentioning

confidence: 99%

Deleterious impact ofPseudomonas aeruginosaon cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

et al. 2015

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The epithelial response to bacterial airway infection, a common feature of lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis, has been extensively studied. However, its impact on cystic fibrosis transmembrane conductance regulator (CFTR) channel function is not clearly defined. Our aims were, therefore, to evaluate the effect of Pseudomonas aeruginosa on CFTR function and expression in non-cystic fibrosis airway epithelial cells, and to investigate its impact on ΔF508-CFTR rescue by the VRT-325 corrector in cystic fibrosis cells.CFTR expression/maturation was evaluated by immunoblotting and its function by short-circuit current measurements.A 24-h exposure to P. aeruginosa diffusible material (PsaDM) reduced CFTR currents as well as total and membrane protein expression of the wildtype (wt) CFTR protein in CFBE-wt cells. In CFBE-ΔF508 cells, PsaDM severely reduced CFTR maturation and current rescue induced by VRT-325. We also confirmed a deleterious impact of PsaDM on wt-CFTR currents in non-cystic fibrosis primary airway cells as well as on the rescue of ΔF508-CFTR function induced by VRT-325 in primary cystic fibrosis cells.These findings show that CFTR function could be impaired in non-cystic fibrosis patients infected by P. aeruginosa. Our data also suggest that CFTR corrector efficiency may be affected by infectious components, which should be taken into account in screening assays of correctors. @ERSpublications Exposure of airway epithelial cell to P. aeruginosa impairs CFTR function, expression and rescue by correctors http://ow.ly/IleTw

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Section: Introductionmentioning

confidence: 99%

Deleterious impact ofPseudomonas aeruginosaon cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

et al. 2015

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“…Using cell-based high-throughout screens, we reported small-molecule ⌬Phe508-CFTR potentiators (Yang et al, 2003;Pedemonte et al, 2005b; benzothiophenes, phenylglycines, and sulfonamides) and correctors (Pedemonte et al, 2005a;Yu et al, 2008;Ye et al, 2010;aminoarylthiazoles and bithiazoles). Subsequent small-scale screening by several groups identified additional candidate potentiators (Van Goor et al, 2006;Pedemonte et al, 2007) and correctors (Noël et al, 2008;Robert et al, 2008Robert et al, , 2010Kalid et al, 2010;Sampson et al, 2011). A potentiator, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770) (Van Goor et al, 2009), and a corrector, VX-809 (Van Goor et al, 2010), identified by Vertex Pharmaceuticals are in clinical trials (Accurso et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Cyanoquinolines with Independent Corrector and Potentiator Activities Restore ΔPhe508-Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Function in Cystic Fibrosis

Phuan¹,

Yang²,

Knapp³

et al. 2011

Mol Pharmacol

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The ⌬Phe508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein impairs its folding, stability, and chloride channel gating. Although small molecules that separately correct defective ⌬Phe508-CFTR folding/cellular processing ("correctors") or chloride channel gating ("potentiators") have been discovered and are in clinical trials, single compounds with bona fide dual corrector and potentiator activities have not been identified. Here, screening of ϳ110,000 small molecules not tested previously revealed a cyanoquinoline class of compounds with independent corrector and potentiator activities (termed CoPo). Analysis of 180 CoPo analogs revealed 6 compounds with dual corrector and potentiator activities and 13 compounds with only potentiator activity. N-(2-((3-Cyano-5,7-dimethylquinolin-2-yl)amino)ethyl)-3-methoxybenzamide (CoPo-22), which was synthesized in six steps in 52% overall yield, had low micromolar EC 50 for ⌬Phe508-CFTR corrector and potentiator activities by short-circuit current assay. Maximal corrector and potentiator activities were comparable with those conferred by the bithiazole Corr-4a and the flavone genistein, respectively. CoPo-22 also activated wild-type and G551D CFTR chloride conductance within minutes in a forskolin-dependent manner. Compounds with dual corrector and potentiator activities may be useful for singledrug treatment of cystic fibrosis caused by ⌬Phe508 mutation.

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“…With a correction response in CFBE cells expressing F508del-CFTR that was 3.2% that of wild-type CFTR, MCG315 is almost 10-fold more potent than the parent molecule latonduine, although MCG315 gave only 35% of the response obtained with VX-809 under the same conditions, which is more potent than many other CFTR correctors (Carlile et al, 2007;Robert et al, 2008;Anjos et al, 2012;Zhang et al, 2012;Sampson et al, 2013). When this is considered in combination with the fact the 10-fold increase in corrector potency was found after studying only seven new analogs, this suggests that the latonduine scaffold and its chemical space should be further explored.…”

Section: Discussionmentioning

confidence: 92%

“…When F508del-CFTR surface expression is restored, it retains some function however its stability in the plasma ABBREVIATIONS: ABT888, 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide; BHK, baby hamster kidney; 4m8C, 7-hydroxy-4-methyl-2-oxochromene-8-carbaldehyde; CF, cystic fibrosis; CFBE, cystic fibrosis bronchial epithelial; CFTR, cystic fibrosis transmembrane conductance regulator; DR2313, DR2313 (2-methyl-1,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidin-4-one); ER, endoplasmic reticulum; HA, hemagglutinin; HEK, human embryonic kidney; HTS, high-throughput screening; IRE-1, inositol-requiring enzyme 1; MCG315, 2,3-dihydro-1H-2-benzazepin-1-one; MCG559,2, membrane and open probability are reduced compared with wild-type channels (Lukacs et al, 1993;Hwang and Sheppard, 2009). The ability of some small molecules to partially restore F508del-CFTR trafficking has encouraged the development of drug candidates (Sato et al, 1996;Rubenstein et al, 1997;Egan et al, 2004;Carlile et al, 2007;Robert et al, 2008Robert et al, , 2010Van Goor et al, 2011;Clancy et al, 2012). However, only VX-809 (Lumacaftor) (Selleckchem, Houston TX) [3-{6-{[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid] and its analog VX-661 [1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide] have progressed to clinical trials (Clancy et al, 2012), with VX-809 having only limited success in restoring F508-del-CFTR function in patients (Grasemann and Ratjen, 2010).…”

Section: Introductionmentioning

confidence: 99%

Latonduine Analogs Restore F508del–Cystic Fibrosis Transmembrane Conductance Regulator Trafficking through the Modulation of Poly-ADP Ribose Polymerase 3 and Poly-ADP Ribose Polymerase 16 Activity

et al. 2016

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Cystic fibrosis (CF) is a major lethal genetic disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR). This encodes a chloride ion channel on the apical surface of epithelial cells. The most common mutation in CFTR (F508del-CFTR) generates a protein that is misfolded and retained in the endoplasmic reticulum. Identifying small molecules that correct this CFTR trafficking defect is a promising approach in CF therapy. However, to date only modest efficacy has been reported for correctors in clinical trials. We identified the marine sponge metabolite latonduine as a corrector. We have now developed a series of latonduine derivatives that are more potent F508del-CFTR correctors with one (MCG315 [2,3-dihydro-1H-2-benzazepin-1-one]) having 10-fold increased corrector activity and an EC 50 of 72.25 nM.We show that the latonduine analogs inhibit poly-ADP ribose polymerase (PARP) isozymes 1, 3, and 16. Further our molecular modeling studies point to the latonduine analogs binding to the PARP nicotinamide-binding domain. We established the relationship between the ability of the latonduine analogs to inhibit PARP-16 and their ability to correct F508del-CFTR trafficking. We show that latonduine can inhibit both PARP-3 and -16 and that this is necessary for CFTR correction. We demonstrate that latonduine triggers correction by regulating the activity of the unfolded protein response activator inositolrequiring enzyme (IRE-1) via modulation of the level of its ribosylation by PARP-16. These results establish latonduines novel site of action as well as its proteostatic mechanism of action.

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Structural Analog of Sildenafil Identified as a Novel Corrector of the F508del-CFTR Trafficking Defect

Cited by 109 publications

References 40 publications

Deleterious impact ofPseudomonas aeruginosaon cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

Deleterious impact ofPseudomonas aeruginosaon cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

Cyanoquinolines with Independent Corrector and Potentiator Activities Restore ΔPhe508-Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Function in Cystic Fibrosis

Latonduine Analogs Restore F508del–Cystic Fibrosis Transmembrane Conductance Regulator Trafficking through the Modulation of Poly-ADP Ribose Polymerase 3 and Poly-ADP Ribose Polymerase 16 Activity

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