Thiophenecarboxylate Suppressor of Cyclic Nucleotides Discovered in a Small-Molecule Screen Blocks Toxin-Induced Intestinal Fluid Secretion

Tradtrantip, Lukmanee; Yangthara, Buranee; Padmawar, Prashant A.; Morrison, Christopher

doi:10.1124/mol.108.050567

Cited by 19 publications

(13 citation statements)

References 30 publications

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“…The library included a set of reference compounds with previously demonstrated activity on CFTR (Sui et al, 2010). We adapted the FRT YFP halide flux assay, first described by Galietta 18 and subsequently used by multiple groups to identify CFTR modulators, [43][44][45][46][47] for increased throughput and compatibility with our combination HTS (cHTSÔ) platform (Sui et al, 2010).…”

Section: Identification Of Modulators Of F508del Cftrmentioning

confidence: 99%

Identification of Synergistic Combinations of F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Lin¹,

Sui

Cotard³

et al. 2010

ASSAY and Drug Development Technologies

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Cystic fibrosis (CF) is an inherited, life-threatening disease caused by mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR), an ABC transporter-class protein and ion channel that transports ions across epithelial cell membranes. The most common mutation leads to the deletion of a single phenylalanine, and the resulting protein, F508del-CFTR, shows reduced trafficking to the membrane and defective channel gating. The ideal therapeutic approach would address both of these defects and restore channel function at the same time. We describe here the application of a combination high-throughput screening to search for synergistic modulators of F508del-CFTR. With the adapted Fischer rat thyroid-yellow fluorescent protein halide flux assay to the combination high-throughput screening platform, we identified many interesting single agents as CFTR modulators from a library of approved drugs and mechanistic probe compounds, and combinations that synergistically modulate F508del-CFTR channel function in Fischer rat thyroid cells, demonstrating the potential for combination therapeutics to address the defects that cause CF.

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Section: Identification Of Modulators Of F508del Cftrmentioning

confidence: 99%

Identification of Synergistic Combinations of F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Lin¹,

Sui

Cotard³

et al. 2010

ASSAY and Drug Development Technologies

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“…Treatments capable of increasing their expression or activity could, therefore, be effective in slowing the development of the disease. 37 …”

Section: /Ws25mentioning

confidence: 99%

Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies

Wang

Sussman

et al. 2015

JASN

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Aberrant intracellular calcium levels and increased cAMP signaling contribute to the development of polycystic kidney disease (PKD). cAMP can be hydrolyzed by various phosphodiesterases (PDEs). To examine the role of cAMP hydrolysis and the most relevant PDEs in the pathogenesis of PKD, we examined cyst development in Pde1-or Pde3-knockout mice on the Pkd2 2/WS25 background (WS25 is an unstable Pkd2 allele). These PDEs were selected because of their importance in cross-talk between calcium and cyclic nucleotide signaling (PDE1), control of cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR) -driven fluid secretion (PDE3), and response to vasopressin V2 receptor activation (both). In Pkd2 2/WS25mice, knockout of Pde1a, Pde1c, or Pde3a but not of Pde1b or Pde3b aggravated the development of PKD and was associated with higher levels of protein kinase Aphosphorylated (Ser133) cAMP-responsive binding protein (P-CREB), activating transcription factor-1, and CREB-induced CRE modulator proteins in kidney nuclear preparations. Immunostaining also revealed higher expression of P-CREB in Pkd2 2/WS25 ;Pde1a 2/2 , Pkd2 2/WS25 ;Pde1c 2/2 , and Pkd2 2/WS25 ;Pde3a 2/2 kidneys.The cystogenic effect of desmopressin administration was markedly enhanced in Pkd2 2/WS25 ;Pde3a 2/2 mice, despite PDE3 accounting for only a small fraction of renal cAMP PDE activity. These observations show that calcium-and calmodulindependent PDEs (PDE1A and PDE1C) and PDE3A modulate the development of PKD, possibly through the regulation of compartmentalized cAMP pools that control cell proliferation and CFTR-driven fluid secretion. Treatments capable of increasing the expression or activity of these PDEs may, therefore, retard the development of PKD.

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“…50 A small-molecule, nonselective PDE activator lowers cAMP and inhibits the growth of MDCK cysts. 51 …”

Section: Disruption Of Intracellular Calcium Homeostasis and Pkdmentioning

confidence: 99%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

243

218

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Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.

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Thiophenecarboxylate Suppressor of Cyclic Nucleotides Discovered in a Small-Molecule Screen Blocks Toxin-Induced Intestinal Fluid Secretion

Cited by 19 publications

References 30 publications

Identification of Synergistic Combinations of F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Identification of Synergistic Combinations of F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

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