| Identification | Back Directory | [Name]
LY2109761 | [CAS]
700874-71-1 | [Synonyms]
LY210976
LY2109761
LY2109761, >=98%
LY2109761/LY-2109761
7-(2-morpholinoethoxy)-4-(2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline
4-(2-(4-(2-(Pyridin-2-yl)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yloxy)e
4-[5,6-Dihydro-2-(2-pyridinyl)-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-[2-(4-morpholinyl)ethoxy]quinoline
4-[2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]oxyethyl]Morpholine
Quinoline, 4-[5,6-dihydro-2-(2-pyridinyl)-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-[2-(4-Morpholinyl)ethoxy]-
4-[5,6-Dihydro-2-(2-pyridinyl)-4H-pyrrolo[1,2-b]pyrazol-3-yl]-7-[2-(4-morpholinyl)ethoxy]quinoline LY 2109761 | [Molecular Formula]
C26H27N5O2 | [MDL Number]
MFCD28142655 | [MOL File]
700874-71-1.mol | [Molecular Weight]
441.525 |
| Chemical Properties | Back Directory | [Boiling point ]
640.9±55.0 °C(Predicted) | [density ]
1.34 | [storage temp. ]
Store at -20°C | [solubility ]
≥22.1 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH | [form ]
solid | [pka]
6.27±0.10(Predicted) |
| Questions And Answer | Back Directory | [Description]
LY2109761 is a novel selective TGF-β receptor type I/II (TβRI/II) dual inhibitor with Ki of 38 nM and 300 nM in a cell-free assay, respectively; shown to negatively affect the phosphorylation of Smad2. | [In vitro]
LY2109761 treatment induces a dose-dependent low-anchorage growth inhibition of L3.6pl/GLT cells, leading to ~33% or 73% inhibition at 2 μM and 20 μM, respectively, which can be strongly enhanced when combined with gemcitabine in combination index value of 0.36581. Blocking TβRI/II kinase activity with LY2109761 (5 μM) completely suppresses both the basal and TGF-β1-stimulated migration and invasion of L3.6pl/GLT cells, significantly enhances the detachment-induced apoptosis by 26% at 8 hours treatment, and completely suppresses TGF-β–induced Smad2 phosphorylation. LY2109761 treatment at 1 nM is sufficient to significantly block the migration and invasion but not adhesion of hepatocellular carcinoma cells by increasing E-cadherin expression. LY2109761 pretreatment enhances radiosensitivity of glioblastoma cells via TGF-β signaling blockage. LY2109761 (10 μM) reduces the self-renewal and proliferation of GBM-derived cancer stem–like cells (CSLC), which can be significantly enhanced when combined with radiation. | [In vivo]
Administration of LY2109761 (50 mg/kg) alone or in combination with gemcitabine (25 mg/kg) significantly reduces the tumor volume by ~70% and ~90%, respectively, prolongs the survival with the median survival duration of 45.0 days and 77.5 days, respectively, and reduces spontaneous abdominal metastases in the L3.6pl/GLT Xenograft mice model. In consistent with the in vitro effect, administration of LY2109761 alone or in combination with radiation, markedly inhibits tumor growth in the orthotopical CSLC glioblastoma model by 43.4% and 76.3%, respectively, decreases tumor invasion and tumor microvessel density, and significantly enhances radiation-induced tumor growth delay in the U87MG xenograft mice model. |
| Hazard Information | Back Directory | [Uses]
LY 2109761 is a novel transforming growth factor beta receptor type I and type II dual inhibitor that is potentially used to treat and suppress pancreatic cancer. | [References]
[1]melisi d, ishiyama s, sclabas gm et al. ly2109761, a novel transforming growth factor beta receptor type i and type ii dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. mol cancer ther 2008; 7: 829-840.
[2]li hy, mcmillen wt, heap cr et al. optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type i receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type i inhibitor as antitumor agent. j med chem 2008; 51: 2302-2306.
[3]xu y, tabe y, jin l et al. tgf-beta receptor kinase inhibitor ly2109761 reverses the anti-apoptotic effects of tgf-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells. br j haematol 2008; 142: 192-201.
[4]zhang m, kleber s, rohrich m et al. blockade of tgf-beta signaling by the tgfbetar-i kinase inhibitor ly2109761 enhances radiation response and prolongs survival in glioblastoma. cancer res 2011; 71: 7155-7167.
[5]flechsig p, dadrich m, bickelhaupt s et al. ly2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of tgf-beta and bmp-associated proinflammatory and proangiogenic signals. clin cancer res 2012; 18: 3616-3627. |
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