LY 303511 dihydrochloride 

LY 303511 dihydrochloride is a structural analogue of LY294002. LY 303511 dihydrochloride does not inhibit PI3K. LY 303511 dihydrochloride enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells. LY 303511 dihydrochloride reversibly blocks K⁺ currents (IC₅₀=64.6±9.1 μM) in MIN6 insulinoma cells.

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.

Intraperitoneal administration of vehicle or LY 303511 dihydrochloride (10 mg/kg/day) is performed when tumors reach a volume of ~150 mm³, at which time 35 mice have developed a tumor. After 21 days, >15% of the mice require euthanasia because of excessive tumor growth, and these data are censored due to unreliable estimates of average tumor volume. The administration of LY 303511 dihydrochloride, 10 mg/kg/day, is sufficient to inhibit PC-3 tumor growth in vivo^[4].

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

379.28

C₁₉H₂₀Cl₂N₂O₂

854127-90-5

O=C1C=C(N2CCNCC2)OC3=C(C4=CC=CC=C4)C=CC=C31.Cl.Cl

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. El-Kholy W, et al. FASEB J. 2003 Apr;17(6):720-2.  [Content Brief]

  [2]. Bodenstine TM, et al. Homotypic gap junctional communication associated with metastasis suppression increases with PKA activity and is unaffected by PI3K inhibition. Cancer Res. 2010 Dec 1;70(23):10002-11.  [Content Brief]

  [3]. Kristof AS, et al. LY303511 (2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one) acts via phosphatidylinositol 3-kinase-independent pathways to inhibit cell proliferation via mammalian target of rapamycin (mTOR)- and non-mTOR-dependent mechanisms. J Pharmacol Exp Ther. 2005 Sep;314(3):1134-43.  [Content Brief]

  [4]. Shenoy K, et al. LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide-mediated mitogen-activated protein kinase activation and up-regulation of death receptors. Cancer Res. 2009 Mar 1;69(5):1941-50.  [Content Brief]