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Beschreibung

A cell-permeable propionitrile compound that targets the CBD (cAMP-binding domain) of EPAC/cAMP-GEF with 4-fold higher affinity than cAMP and selectively inhibits cAMP-dependent EPAC GEF activity (IC50 = 1.4 and 3.2 M, respectively, against EPAC2 and EPAC1, [cAMP] = 25 M) with much reduced potency toward cAMP-dependent PKA activity (10% and 20% inhibition at 100 M, respectively, against 100 M cAMP-stimulated Type Ialpha and IIbeta PKA activity). Shown to block both basal and 8-CPT-2'-O-Me-cAMP (Cat. No. 116833) prodrug 007-AM-, but not EGF-, stimulated Akt phosphorylations in serum-starved human AsPC-1 (>=185%, <=85%, and <10% of basal thr308/Ser473 phosphorylation, respectively, with 0, 1, 10 M ESI-09, [007-AM] = 10 M) and EPAC-mediated insulin secretion from rat INS-1 cells (IC50<5 M, [007-AM] = 10 M)., A cell-permeable, propionitrile compound that targets the CBD (cAMP-binding domain) of EPAC/cAMP-GEF with 4-fold higher affinity than cAMP (IC50 = 10 vs. 39 µ,M, respectively, against 8-NBD-cAMP in competition EPAC2 binding assay) and selectively inhibits cAMP-dependent EPAC GEF activity (IC50 = 1.4 and 3.2 µ,M, respectively, against EPAC2 and EPAC1, [cAMP] = 25 µ,M) with much reduced potency toward cAMP-dependent PKA activity (10% and 20% inhibition at 100 µ,M, respectively, against 100 µ,M cAMP-stimulated Type Ialpha and IIbeta PKA activity). Shown to block both basal and 8-CPT-2'-O-Me-cAMP (Cat. No. 116833) prodrug 007-AM-stimulated Akt thr308/Ser473 phosphorylations in serum-starved human pancreatic cancer AsPC-1 (%thr308/%Ser473 of basal phosphorylation = 200%/185%, 85%/65%, and <10%/<10%, respectively, with 0, 1, 10 µ,M ESI-09, [007-AM] = 10 µ,M) and rat pancreatic beta-cell INS-1 without affecting EGF-stimulated Akt phosphorylations, resulting in effective inhibition of EPAC-mediated insulin secretion from INS-1 cells (by 57% and 100%, respectively, at 5 and 10 µ,M, [007-AM] = 10 µ,M) and pancreatic cancer cell invasion (~60% inhibition at 5 µ,M using AsPC-1 and PANC-1 cells)., A cell-permeable compound that targets cAMP-binding domain of EPAC/cAMP-GEF and inhibits cAMP-dependent EPAC GEF activity (IC₅,₀, = 1.4 and 3.2 µ,M, respectively, against EPAC2 and EPAC1).