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A. S. Verkman - One of the best experts on this subject based on the ideXlab platform.
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synergy based small molecule screen using a human lung epithelial cell line yields δf508 cftr Correctors that augment vx 809 maximal efficacy
Molecular Pharmacology, 2014Co-Authors: Puay-wah Phuan, Guido Veit, Ariel Roldan, Walter E Finkbeiner, Gergely L Lukacs, A. S. VerkmanAbstract:The most prevalent cystic fibrosis transmembrane conductance regulator (CFTR) mutation causing cystic fibrosis, ΔF508, impairs folding of nucleotide binding domain (NBD) 1 and stability of the interface between NBD1 and the membrane-spanning domains. The interfacial stability defect can be partially corrected by the investigational drug VX-809 (3-[6-[[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-3-methyl-2-pyridinyl]-benzoic acid) or the R1070W mutation. Second-generation ΔF508-CFTR Correctors are needed to improve on the modest efficacy of existing cystic fibrosis Correctors. We postulated that a second Corrector targeting a distinct folding/interfacial defect might act in synergy with VX-809 or the R1070W suppressor mutation. A biochemical screen for ΔF508-CFTR cell surface expression was developed in a human lung epithelium–derived cell line (CFBE41o−) by expressing chimeric CFTRs with a horseradish peroxidase (HRP) in the fourth exofacial loop in either the presence or absence of R1070W. Using a luminescence readout of HRP activity, screening of approximately 110,000 small molecules produced nine novel Corrector scaffolds that increased cell surface ∆F508-CFTR expression by up to 200% in the presence versus absence of maximal VX-809. Further screening of 1006 analogs of compounds identified from the primary screen produced 15 Correctors with an EC50
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Structure–Activity Relationships of Cyanoquinolines with Corrector–Potentiator Activity in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein
2012Co-Authors: John M. Knapp, Alex B. Wood, Puay-wah Phuan, Michael W. Lodewyk, Dean J. Tantillo, A. S. Verkman, Mark J KurthAbstract:Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both Corrector (“Co”, normalizing ΔF508-CFTR targeting) and potentiator (“Po”, normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for Corrector and potentiator activities. Compounds with potentiator-only, Corrector-only, and dual potentiator–Corrector activities were found. Molecular modeling studies (conformational search ⇒ force-field lowest energy assessment ⇒ geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo’s may adopt two distinct π-stacking conformations to elicit Corrector and potentiator activities
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cyanoquinolines with independent Corrector and potentiator activities restore δphe508 cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis
Molecular Pharmacology, 2011Co-Authors: Puay-wah Phuan, Mark J Kurth, Baoxue Yang, John M. Knapp, Alex B. Wood, Gergely L Lukacs, A. S. VerkmanAbstract:The ΔPhe508 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 ΔPhe508-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 ∼110,000 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 EC50 for ΔPhe508-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 single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation.
Mark J Kurth - One of the best experts on this subject based on the ideXlab platform.
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Structure–Activity Relationships of Cyanoquinolines with Corrector–Potentiator Activity in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein
2012Co-Authors: John M. Knapp, Alex B. Wood, Puay-wah Phuan, Michael W. Lodewyk, Dean J. Tantillo, A. S. Verkman, Mark J KurthAbstract:Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both Corrector (“Co”, normalizing ΔF508-CFTR targeting) and potentiator (“Po”, normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for Corrector and potentiator activities. Compounds with potentiator-only, Corrector-only, and dual potentiator–Corrector activities were found. Molecular modeling studies (conformational search ⇒ force-field lowest energy assessment ⇒ geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo’s may adopt two distinct π-stacking conformations to elicit Corrector and potentiator activities
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cyanoquinolines with independent Corrector and potentiator activities restore δphe508 cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis
Molecular Pharmacology, 2011Co-Authors: Puay-wah Phuan, Mark J Kurth, Baoxue Yang, John M. Knapp, Alex B. Wood, Gergely L Lukacs, A. S. VerkmanAbstract:The ΔPhe508 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 ΔPhe508-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 ∼110,000 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 EC50 for ΔPhe508-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 single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation.
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sulfamoyl 4 oxoquinoline 3 carboxamides novel potentiators of defective δf508 cystic fibrosis transmembrane conductance regulator chloride channel gating
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Yat Fan Suen, Michael H Nantz, Lori I. Robins, Baoxue Yang, Mark J KurthAbstract:Abstract The synthesis of a small collection of sulfamoyl-4-oxoquinoline-3-carboxamides is described for use as Correctors of defective gating of the ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Several compounds with submicromolar potency were obtained. N -Ethyl 6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide ( 7b ) was found to be the most effective sulfonamide Corrector of defective ΔF508-CFTR gating.
Puay-wah Phuan - One of the best experts on this subject based on the ideXlab platform.
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synergy based small molecule screen using a human lung epithelial cell line yields δf508 cftr Correctors that augment vx 809 maximal efficacy
Molecular Pharmacology, 2014Co-Authors: Puay-wah Phuan, Guido Veit, Ariel Roldan, Walter E Finkbeiner, Gergely L Lukacs, A. S. VerkmanAbstract:The most prevalent cystic fibrosis transmembrane conductance regulator (CFTR) mutation causing cystic fibrosis, ΔF508, impairs folding of nucleotide binding domain (NBD) 1 and stability of the interface between NBD1 and the membrane-spanning domains. The interfacial stability defect can be partially corrected by the investigational drug VX-809 (3-[6-[[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-3-methyl-2-pyridinyl]-benzoic acid) or the R1070W mutation. Second-generation ΔF508-CFTR Correctors are needed to improve on the modest efficacy of existing cystic fibrosis Correctors. We postulated that a second Corrector targeting a distinct folding/interfacial defect might act in synergy with VX-809 or the R1070W suppressor mutation. A biochemical screen for ΔF508-CFTR cell surface expression was developed in a human lung epithelium–derived cell line (CFBE41o−) by expressing chimeric CFTRs with a horseradish peroxidase (HRP) in the fourth exofacial loop in either the presence or absence of R1070W. Using a luminescence readout of HRP activity, screening of approximately 110,000 small molecules produced nine novel Corrector scaffolds that increased cell surface ∆F508-CFTR expression by up to 200% in the presence versus absence of maximal VX-809. Further screening of 1006 analogs of compounds identified from the primary screen produced 15 Correctors with an EC50
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Structure–Activity Relationships of Cyanoquinolines with Corrector–Potentiator Activity in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein
2012Co-Authors: John M. Knapp, Alex B. Wood, Puay-wah Phuan, Michael W. Lodewyk, Dean J. Tantillo, A. S. Verkman, Mark J KurthAbstract:Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both Corrector (“Co”, normalizing ΔF508-CFTR targeting) and potentiator (“Po”, normalizing ΔF508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for Corrector and potentiator activities. Compounds with potentiator-only, Corrector-only, and dual potentiator–Corrector activities were found. Molecular modeling studies (conformational search ⇒ force-field lowest energy assessment ⇒ geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo’s may adopt two distinct π-stacking conformations to elicit Corrector and potentiator activities
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cyanoquinolines with independent Corrector and potentiator activities restore δphe508 cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis
Molecular Pharmacology, 2011Co-Authors: Puay-wah Phuan, Mark J Kurth, Baoxue Yang, John M. Knapp, Alex B. Wood, Gergely L Lukacs, A. S. VerkmanAbstract:The ΔPhe508 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 ΔPhe508-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 ∼110,000 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 EC50 for ΔPhe508-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 single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation.
Baoxue Yang - One of the best experts on this subject based on the ideXlab platform.
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cyanoquinolines with independent Corrector and potentiator activities restore δphe508 cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis
Molecular Pharmacology, 2011Co-Authors: Puay-wah Phuan, Mark J Kurth, Baoxue Yang, John M. Knapp, Alex B. Wood, Gergely L Lukacs, A. S. VerkmanAbstract:The ΔPhe508 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 ΔPhe508-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 ∼110,000 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 EC50 for ΔPhe508-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 single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation.
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sulfamoyl 4 oxoquinoline 3 carboxamides novel potentiators of defective δf508 cystic fibrosis transmembrane conductance regulator chloride channel gating
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Yat Fan Suen, Michael H Nantz, Lori I. Robins, Baoxue Yang, Mark J KurthAbstract:Abstract The synthesis of a small collection of sulfamoyl-4-oxoquinoline-3-carboxamides is described for use as Correctors of defective gating of the ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Several compounds with submicromolar potency were obtained. N -Ethyl 6-(ethylphenylsulfamoyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide ( 7b ) was found to be the most effective sulfonamide Corrector of defective ΔF508-CFTR gating.
David M Clarke - One of the best experts on this subject based on the ideXlab platform.
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Corrector vx 809 stabilizes the first transmembrane domain of cftr
Biochemical Pharmacology, 2013Co-Authors: Claire M Bartlett, David M ClarkeAbstract:Abstract Processing mutations that inhibit folding and trafficking of CFTR are the main cause of cystic fibrosis (CF). A potential CF therapy would be to repair CFTR processing mutants. It has been demonstrated that processing mutants of P-glycoprotein (P-gp), CFTR's sister protein, can be efficiently repaired by a drug-rescue mechanism. Many arginine suppressors that mimic drug-rescue have been identified in the P-gp transmembrane (TM) domains (TMDs) that rescue by forming hydrogen bonds with residues in adjacent helices to promote packing of the TM segments. To test if CFTR mutants could be repaired by a drug-rescue mechanism, we used truncation mutants to test if Corrector VX-809 interacted with the TMDs. VX-809 was selected for study because it is specific for CFTR, it is the most effective Corrector identified to date, but it has limited clinical benefit. Identification of the VX-809 target domain will help to develop Correctors with improved clinical benefits. It was found that VX-809 rescued truncation mutants lacking the NBD2 and R domains. When the remaining domains (TMD1, NBD1, TMD2) were expressed as separate polypeptides, VX-809 only increased the stability of TMD1. We then performed arginine mutagenesis on TM6 in TMD1. Although the results showed that TM6 had distinct lipid and aqueous faces, CFTR was different from P-gp as no arginine promoted maturation of CFTR processing mutants. The results suggest that TMD1 contains a VX-809 binding site, but its mechanism differed from P-gp drug-rescue. We also report that V510D acts as a universal suppressor to rescue CFTR processing mutants.
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additive effect of multiple pharmacological chaperones on maturation of cftr processing mutants
Biochemical Journal, 2007Co-Authors: Ying Wang, Tip W Loo, Claire M Bartlett, David M ClarkeAbstract:The most common cause of CF (cystic fibrosis) is the deletion of Phe(508) (DeltaF508) in the CFTR [CF TM (transmembrane) conductance regulator] chloride channel. One major problem with DeltaF508 CFTR is that the protein is defective in folding so that little mature protein is delivered to the cell surface. Expression of DeltaF508 CFTR in the presence of small molecules known as Correctors or pharmacological chaperones can increase the level of mature protein. Unfortunately, the efficiency of Corrector-induced maturation of DeltaF508 CFTR is probably too low to have therapeutic value and approaches are needed to increase maturation efficiency. We postulated that expression of DeltaF508 CFTR in the presence of multiple Correctors that bound to different sites may have an additive effect on maturation. In support of this mechanism, we found that expression of P-glycoprotein (CFTR's sister protein) processing mutants in the presence of two compounds that bind to different sites (rhodamine B and Hoechst 33342) had an additive effect on maturation. Therefore we tested whether expression of DeltaF508 CFTR in the presence of combinations of three different classes of Corrector molecules would increase its maturation efficiency. It was found that the combination of the quinazoline VRT-325 together with the thiazole corr-2b or bisaminomethylbithiazole corr-4a doubled the steady-state maturation efficiency of DeltaF508 CFTR (approx. 40% of total CFTR was mature protein) compared with expression in the presence of a single compound. The additive effect of the Correctors on DeltaF508 CFTR maturation suggests that they directly interact at different sites of the protein.
