title: CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds.
abstract: Activators of the CFTR Cl- channel may be useful for therapy of cystic fibrosis. Short-circuit current (Isc) measurements were done on human bronchial epithelial cells to characterize the best flavone and benzimidazolone CFTR activators identified by lead-based combinatorial synthesis and high-throughput screening. The 7,8-benzoflavone UCcf-029 was a potent activator of Cl- transport, with activating potency (<1 microM) being much better than other flavones, such as apigenin. The benzimidazolone UCcf-853 gave similar Isc but with lower potency (5-20 microM). In combination, the effect induced by maximal UCcf-029 and UCcf-029, UCcf-853, and apigenin increased strongly with increasing basal CFTR activity: for example, Kd for activation by UCcf-029 decreased from >5 to <0.4 microM with increasing basal Isc from approximately 4 microA/cm2 to approximately 12 microA/cm2. This dependence was confirmed in permeabilized Fischer rat thyroid cells stably expressing CFTR. Our results demonstrate efficacy of novel CFTR activators in bronchial epithelia and provide evidence that activating potency depends on basal CFTR activity.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go Gerolamo Gaslini, 5, 16148 Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Caci
authors.forename: Chiara
authors.initials: C
authors.lastname: Folli
authors.forename: Olga
authors.initials: O
authors.lastname: Zegarra-Moran
authors.forename: Tonghui
authors.initials: T
authors.lastname: Ma
authors.forename: Mark F
authors.initials: MF
authors.lastname: Springsteel
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sammelson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nantz
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D047310:Apigenin; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001571:Benzoflavones / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001980:Bronchi / Q000166:cytology; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004232:Diuretics / Q000494:pharmacology; D004357:Drug Synergism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001571:Benzoflavones; C505032:CFTR protein, human; D002712:Chlorides; D004232:Diuretics; D005419:Flavonoids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C014353:benzimidazolone; C011512:alpha-naphthoflavone; D000584:Amiloride; D047310:Apigenin