LY 303511 dihydrochloride

LY 303511 dihydrochloride is structurally identical to LY294002 except for a substitution of -O for -NH in the morpholine ring, and does not potently inhibit PI3K. Treatment of cells with LY 303511 dihydrochloride causes an increase in calcein spread similar to levels of LY294002. The ability of LY 303511 dihydrochloride to increase gap junctional intercellular communication (GJIC) does not occur concomitant with inhibition of phosphorylation of AKT as measured by immunoblotting^[1]. LY 303511 dihydrochloride enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via H₂O₂-MAPK activation and up-regulation of death receptors. SHEP-1 cells are exposed to varying concentrations of LY 303511 dihydrochloride (LY30), TRAIL, and a combination of the two (1 h preincubation with LY 303511 dihydrochloride followed by TRAIL for 4 hours). SHEP-1 cells are responsive to TRAIL (~10%, ~15%, and ~30% reduction in the surviving fraction at 25, 50, and 100 ng/mL, respectively); however, treatment with LY 303511 dihydrochloride (12.5, 25, or 50 μM) has no effect on cell viability. However, incubation of cells with LY 303511 dihydrochloride (25 μM) for 1 hour followed by 4 hours exposure to 50 ng/mL of TRAIL has a strong synergistic effect (~40% reduction in viable cells with LY 303511 dihydrochloride+TRAIL versus ~15% with TRAIL alone)^[2]. LY 303511 dihydrochloride is a negative control compound with respect to PI3K activity. In MIN6 insulinoma cells, Wortmannin (100 nM) has no effect on whole-cell outward K⁺ currents, but LY294002 and LY 303511 dihydrochloride reversibly block currents in a dose-dependent manner (IC₅₀=9.0±0.7 μM and 64.6±9.1 μM, respectively). Kv2.1 and Kv1.4 are highly expressed in beta-cells, and in Kv2.1-transfected tsA201 cells, 50 μM LY294002 and 100 μM LY 303511 dihydrochloride reversibly inhibit currents by 99% and 41%, respectively. LY 303511 dihydrochloride blocks currents with an IC₅₀ of 64.6±9.1 μM, with a maximal inhibition of ~90% at 500 μM (n≥5 cells at each concentration)^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.