LY2109761 is a highly potent and selective TGFβ receptor type I and type II (TβRI/II) inhibitor with Ki of 38 nM and 300 nM respectively. Blocking TβRI/II kinase activity with LY2109761 completely suppresses both the basal and TGF-β1-stimulated migration and invasion of L3.6pl/GLT cells, 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. It can also reduce the self-renewal and proliferation of GBM-derived cancer stem–like cells, which can be significantly enhanced when combined with radiation. Administration of LY2109761 alone or in combination with gemcitabine or with radiation demonstrated very good efficacy in multiple xenograft mice models.
CAS Number: 700874-71-1
Molecular Weight: 441.52
Chemical Name: 4-(2-((4-(2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl)oxy)ethyl)morpholine
Appearance: Solid Power.
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: DMSO up to 100 mM
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥360 days if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
LY2109761 was usually used at 5-10 µM in vitro and in cellular assays.
LY2109761 was orally dosed to mice at 50 mg/kg once per day or in combination with gemcitabine (25 mg/kg) to significantly reduce the tumor volume.
- Li HY, 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. (2008) J Med Chem. 51(7):2302-6.
- Melisi D, 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. (2008) Mol Cancer Ther. 7(4):829-40.
- Zhang B, et al. Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. (2009) Cancer Lett. 277(1):114-20.
- Connolly EC, et al. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TβRI/II kinase inhibition with LY2109761. (2011) Cancer Res. 71(6):2339-49.
- Zhang M, et al. Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. (2011) Cancer Res. 71(23):7155-67.
- Flechsig P, et al. LY2109761 Attenuates Radiation-Induced Pulmonary Murine Fibrosis via Reversal of TGF-β and BMP-Associated Proinflammatory and Proangiogenic Signals. (2012) Clin Cancer Res. 18(13):3616-27
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