ABCC1 p.Ile152Leu
| Predicted by SNAP2: | A: N (78%), C: N (78%), D: N (53%), E: N (87%), F: N (61%), G: N (61%), H: N (61%), K: N (87%), L: N (78%), M: N (87%), N: N (82%), P: N (87%), Q: N (93%), R: N (82%), S: N (82%), T: N (87%), V: N (87%), W: D (71%), Y: N (57%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Thiophenecarboxylate suppressor of cyclic nucleoti... Mol Pharmacol. 2009 Jan;75(1):134-42. Epub 2008 Sep 29. Tradtrantip L, Yangthara B, Padmawar P, Morrison C, Verkman AS
Thiophenecarboxylate suppressor of cyclic nucleotides discovered in a small-molecule screen blocks toxin-induced intestinal fluid secretion.
Mol Pharmacol. 2009 Jan;75(1):134-42. Epub 2008 Sep 29., [PMID:18824527]
Abstract [show]
We carried out a "pathway" screen of 50,000 small molecules to identify novel modulators of cAMP signaling. One class of compounds, the 2-(acylamino)-3-thiophenecarboxylates, strongly suppressed cAMP and cGMP in multiple cell lines in response to different agonists acting on G-protein-coupled receptors, adenylyl cyclase, and guanylyl cyclase. The best compounds from structure-activity analysis of 124 analogs, including several synthesized chiral analogs, had and IC(50) of <5 microM for suppression of agonist-induced cAMP and cGMP elevation. Measurements of cAMP, cGMP, and downstream signaling in response to various activators/inhibitors suggested that the 2-(acylamino)-3-thiophenecarboxylates function as nonselective phosphodiesterase activators, although it was not determined whether their action on phosphodiesterases is direct or indirect. The 2-(acylamino)-3-thiophenecarboxylates suppressed CFTR-mediated Cl(-) current in T84 colonic cells in response to cholera and Escherichia coli (STa) toxins, and prevented intestinal fluid accumulation in a closed-loop mouse model of secretory diarrhea. They also prevented cyst growth in an in vitro renal epithelial cell model of polycystic kidney disease. The 2-(acylamino)-3-thiophenecarboxylates represent the first small-molecule cyclic nucleotide suppressors, whose potential therapeutic indications include secretory diarrheas, polycystic kidney disease, and growth inhibition of cAMP-dependent tumors.
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No. Sentence Comment
35 Fisher rat thyroid (FRT) cells expressing human wild-type CFTR and YFP-H148Q/I152L, with or without V2R, were generated as described previously (Yangthara et al., 2007).
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ABCC1 p.Ile152Leu 18824527:35:77
status: NEW45 Transfected FRT cells were plated on black 96-well plates with clear plastic bottoms (Costar; Corning Life Science, Acton, MA), cultured overnight to confluence, washed three times with PBS, and treated with test compounds in a final volume of 60 l. YFP-H148Q/I152L fluorescence was measured using a commercial plate-reader (FluoStar Optima; BMG Labtech, Winooski, VT) equipped with custom excitation and emission filters (500 nm and 544 nm, respectively; Chroma Technology Corp., Brattleboro, VT).
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ABCC1 p.Ile152Leu 18824527:45:268
status: NEW130 A primary screen of 50,000 small molecules was done on FRT cells stably expressing human wild-type V2R and CFTR, and the fluorescent halide sensor YFP-H148Q/I152L.
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ABCC1 p.Ile152Leu 18824527:130:157
status: NEW