Discovery of Pyrrolo[2,3-b]pyrazines Derivatives as Submicromolar Affinity Activators of Wild Type, G551D, and F508del Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels

Noël, Sabrina; Faveau, Christelle; Norez, Caroline; Rogier, Christian; Mettey, Yvette; Becq, Frédéric

doi:10.1124/jpet.106.104521

Cited by 38 publications

(33 citation statements)

References 39 publications

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“…The forskolin-activated I/V relationship exhibited a linear profile typical for CFTR and was completely inhibited by the specific inhibitor CFTR inh -172 (5 μmol/L; refs. 34,35). Addition of cisplatin (60 μg/mL) remained without effect on the forskolinstimulated current (n = 4; Fig.…”

Section: Cisplatin and Ion Channelsmentioning

confidence: 99%

Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling

et al. 2010

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Cisplatin is an antineoplastic drug, mostly documented to cause cell death through the formation of DNA adducts. In patients, it exhibits a range of short-term side effects that are unlikely to be related to its genomic action. As cisplatin has been shown to modify membrane properties in different cell systems, we investigated its effects on mechanosensitive ion transporters and channels. We show here that cisplatin is a noncompetitive inhibitor of the mechanosensitive Na + /H + exchanger NHE-1, with a half-inhibition concentration of 30 μg/mL associated with a decrease in V max and Hill coefficient. We also showed that it blocks the Cl − and K + mechanosensitive channels VSORC and TREK-1 at similar concentrations. In contrast, the nonmechanosensitive Cl − and K + channels CFTR and TASK-1 and the Na + -coupled glucose transport, which share functional features with VSORC, TREK-1, and NHE-1, respectively, were insensitive to cisplatin. We next investigated whether cisplatin action was due to a direct effect on membrane or to cortical actin remodeling that would affect mechanosensors. Using scanning electron microscopy, in vivo actin labeling, and atomic force microscopy, we did not observe any modification of the Young's modulus and actin cytoskeleton for up to 60 and 120 μg/mL cisplatin, whereas these concentrations modified membrane morphology. Our results reveal a novel mechanism for cisplatin, which affects mechanosensitive channels and transporters involved in cell fate programs and/or expressed in mechanosensitive organs in which cisplatin elicits strong secondary effects, such as the inner ear or the peripheral nervous system. These results might constitute a common denominator to previously unrelated effects of this drug.

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Section: Cisplatin and Ion Channelsmentioning

confidence: 99%

Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling

et al. 2010

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“…Two well-characterized families of F508del-CFTR potentiators are the xanthines, notably 1,3-diallyl-8-cyclohexylxanthine and 3,7-dimethyl-1-isobutyl xanthine, and the flavones, such as genistein, apigenin, and kaempferol (Drumm et al, 1991;Hwang et al, 1997;Al-Nakkash and Hwang, 1999;Hwang and Sheppard, 1999;Lim et al, 2004). Other potentiators include tetrahydrobenzothiophene, phenylglycine, sulfonamide, and derivatives of pyrrolo [2,3-b]pyrazines (Al-Nakkash and Hwang and Sheppard, 1999;Yang et al, 2003;Pedemonte et al, 2005b;Noel et al, 2006). Fewer correctors have been reported, and some of these (e.g., 4-phenylbutyrate and curcumin) partially correct the processing defect in vitro but are less efficacious when used in vivo (Rubenstein et al, 1997;Rubenstein and Zeitlin, 1998;Egan et al, 2004;Mall and Kunzelmann, 2005).…”

mentioning

confidence: 99%

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

Robert¹,

Carlile

Pavel

et al. 2008

Molecular Pharmacology

109

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“…The xanthines activators are purine heterocycles substituted with hydrophobic substituents attached to a nitrogen atom on the purine (methyl, cyclohexyl, cyclopentadienyl, isopropyl) [6]. Hydrophobic substituents attached to a nitrogen atom also are present in pyrrolo [2,3-b]pyrazines (butyl in RP107 and RP108) [15] and in the benzimidazolones activators (ethyl in 1-EBIO and DCEBIO) [6]. These activators are made of two fused 6-member and 5-member rings like the purine heterocycle in GPact-11a.…”

Section: Structural Determinants For Cftr Activationmentioning

confidence: 99%

“…Cell lines were cultured as previously described: Chinese hamster ovary (CHO), Calu-3, JME/CF15 [15], CF-KM4 and MM39 [16], NuLi and CuFi-1 [17] and CFPAC-1 [18]. HEK293 cells were cultured and transiently transfected with the pEGFP-CFTR wt or F508del as already described [19,20].…”

Section: Cell Culturementioning

confidence: 99%

“…The apical membrane Cl -current was measured on mice colonic epithelium as already described [15] or after a depolarisation protocol [23] using a serosal-to-mucosal gradient with the following bath solution: apical, 107 mM K-gluconate, 4.5 mM KCl, 25 mM NaHCO 3 ,1 mM MgSO 4 , 1.8 mM Na 2 HPO 4 , 0.2 mM NaH 2 PO 4 , 5.75 mM Ca-gluconate, 12 mM D-glucose; basolateral, 111.5 mM KCl, 25 mM NaHCO 3 , 1 mM…”

Section: Short-circuit Current Measurementsmentioning

confidence: 99%

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Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a

Bertrand¹,

Boucherle²,

Billet³

et al. 2010

Eur Respir J

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One of the major therapeutic strategy in cystic fibrosis aims at developing modulators of cystic fibrosis transmembrane conductance regulator (CFTR) channels. We recently discovered methylglyoxal a-aminoazaheterocycle adducts, as a new family of CFTR inhibitors. In a structure-activity relationship study, we have now identified GPact-11a, a compound able not to inhibit but to activate CFTR.Here, we present the effect of GPact-11a on CFTR activity using in vitro (iodide efflux, fluorescence imaging and patch-clamp recordings), ex vivo (short-circuit current measurements) and in vivo (salivary secretion) experiments.We report that GPact-11a: 1) is an activator of CFTR in several airway epithelial cell lines; 2) activates rescued F508del-CFTR in nasal, tracheal, bronchial, pancreatic cell lines and in human CF ciliated epithelial cells, freshly dissociated from lung samples; 3) stimulates ex vivo the colonic chloride secretion and increases in vivo the salivary secretion in cftr +/+ but not cftr -/-mice; and 4) is selective for CFTR because its effect is inhibited by CFTR inh -172, GlyH-101, glibenclamide and GPinh-5a. To conclude, this work identifies a selective activator of wild-type and rescued F508del-CFTR. This nontoxic and water-soluble agent represents a good candidate, alone or in combination with a F508del-CFTR corrector, for the development of a CFTR modulator in cystic fibrosis.

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Discovery of Pyrrolo[2,3-b]pyrazines Derivatives as Submicromolar Affinity Activators of Wild Type, G551D, and F508del Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels

Cited by 38 publications

References 39 publications

Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling

Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling

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

Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a

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