Cas：154447-38-8 (free base)
LY303511, also known as NV-128 and EM 101, is a potent mTOR inhibitor. LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide-mediated mitogen-activated protein kinase activation and up-regulation of death receptors. LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and mitochondrial permeabilization. LY303511 acts via phosphatidylinositol 3-kinase-independent pathways to inhibit cell proliferation via mammalian target of rapamycin (mTOR)- and non-mTOR-dependent mechanisms.
Chemical Formula: C19H18N2O2
Exact Mass: 306.13683
Molecular Weight: 306.365
Elemental Analysis: C, 74.49; H, 5.92; N, 9.14; O, 10.44
InChi Code: InChI=1S/C19H18N2O2/c22-17-13-18(21-11-9-20-10-12-21)23-19-15(7-4-8-16(17)19)14-5-2-1-3-6-14/h1-8,13,20H,9-12H2
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
LY303511 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 LY303511 causes an increase in calcein spread similar to levels of LY294002. The ability of LY303511 to increase gap junctional intercellular communication (GJIC) does not occur concomitant with inhibition of phosphorylation of AKT as measured by immunoblotting.
LY303511 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 LY303511 (LY30), TRAIL, and a combination of the two (1 h preincubation with LY303511 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 LY303511 (12.5, 25, or 50 μM) has no effect on cell viability. However, incubation of cells with LY303511 (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 LY303511+TRAIL versus ~15% with TRAIL alone).
LY303511 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 LY303511 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 LY303511 reversibly inhibit currents by 99% and 41%, respectively.
LY303511 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).
Intraperitoneal administration of vehicle or LY303511 (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 LY303511, 10 mg/kg/day, is sufficient to inhibit PC-3 tumor growth in vivo.
Shi Y, Mellier G, Huang S, White J, Pervaiz S, Tucker-Kellogg L. Computational modelling of LY303511 and TRAIL-induced apoptosis suggests dynamic regulation of cFLIP. Bioinformatics. 2013 Feb 1;29(3):347-54. doi: 10.1093/bioinformatics/bts702. Epub 2012 Dec 13. PubMed PMID: 23239672; PubMed Central PMCID: PMC3562069.
Tucker-Kellogg L, Shi Y, White JK, Pervaiz S. Reactive oxygen species (ROS) and sensitization to TRAIL-induced apoptosis, in Bayesian network modelling of HeLa cell response to LY303511. Biochem Pharmacol. 2012 Nov 15;84(10):1307-17. doi: 10.1016/j.bcp.2012.08.028. Epub 2012 Sep 6. PubMed PMID: 22982511.
Shenoy K, Wu Y, Pervaiz S. 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. doi: 10.1158/0008-5472.CAN-08-1996. Epub 2009 Feb 17. Erratum in: Cancer Res. 2012 Jan 1;72(1):375. PubMed PMID: 19223550.
Poh TW, Huang S, Hirpara JL, Pervaiz S. LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and mitochondrial permeabilization. Cell Death Differ. 2007 Oct;14(10):1813-25. Epub 2007 Jun 22. PubMed PMID: 17585340.
Poh TW, Pervaiz S. LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-Akt pathway. Cancer Res. 2005 Jul 15;65(14):6264-74. PubMed PMID: 16024628.
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