LY2109761

Biological Activity

LY2109761 is a Transforming Growth Factor β (TGF-β) type I /II receptor (TβRI/TβRII) kinase inhibitor with Ki of 38 nM and 300 nM, respectively. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-beta1-induced cell migration and invasion, and induced anoikis. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ.

Product Citations

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  Toxicology. 2022 Oct;480:153338.

  Polystyrene nanoplastics exacerbate lipopolysaccharide-induced myocardial fibrosis and autophagy in mice via ROS/TGF-β1/Smad
  LY2109761 purchased from AbMole

• 

  Molecules. 2021 Apr 13;26(8):2231.

  F4/80 + Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway
  LY2109761 purchased from AbMole

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  Brain Res Bull. 2020 May 8;161:21-32.

  TGFβ1 Alleviates Axonal Injury by Regulating Microglia/Macrophages Alternative Activation in Traumatic Brain Injury
  LY2109761 purchased from AbMole

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  Int Immunopharmacol. 2018 Dec 17;67:287-293.

  Effect of recombinant human thrombopoietin on immune thrombocytopenia in pregnancy in a murine model.
  LY2109761 purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Dissertaion (2015). Figure 3.5. LY2109761 was obtained from abmole (AbMole, Houston, TX).
	Method	western blot
	Cell Lines	mesenchymal/stem cell tumor
	Concentrations	50mg/kg LY2109761 twice every day
	Incubation Time	two weeks
	Results	LY2109761 significantly decreased the expression levels of ZEB2, VCAN, THY1, CDK6, SOX2 and GLI2, even in the presence of TMZ/IR, demonstrating the key role of the TGF-β signaling pathway in regulating mesenchymal and stem cells markers.

Protocol (for reference only)

Cell Experiment
Cell lines	Colo357FG/GLT and Colo357L3.6pl/GLT cells
Preparation method	LY2109761 was dissolved in 100% DMSO at a stock concentration of 10 mmol/L. The concentration of DMSO did not exceed 0.1% in any assay. FG/GLT nonmetastatic pancreatic carcinoma cells (A) and their highly metastatic subclone L3.6pl/GLT pancreatic carcinoma cells were seeded at a density of 1.0 × 103 per well. On the following day, the cells were treated with increasing doses of LY2109761 (0.1, 1, and 10 μmol/L), gemcitabine (0.3, 3,and 30 nmol/L), and their combinations. On day 2, the medium containing drugs was removed, the cells were washed twice with PBS, and fresh medium was added. After 5 d of incubation, the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to obtain relative variable cell numbers. DMSO-treated cells were assigned a value of 100%. Means and 95% confidence intervals of three independent experiments performed in triplicate.
Concentrations	0, 2, 20 µ M
Incubation time	5 days

Animal Experiment
Animal models	Human Pancreatic Carcinoma Tumors Growing in the Pancreas of Athymic Nude Mice
Formulation	dissolved in the SX-1292 oral vehicle (1% sodium carboxymethylcellulose, 0.5% sodium lauryl sulfate, and 0.05% antifoam; Eli Lilly)
Dosages	LY2109761 (50 mg/kg) twice a day p.o. (days 1–5 of each week)
Administration	p.o.

Chemical Information

Molecular Weight	441.52
Formula	C26H27N5O2
CAS Number	700874-71-1
Solubility (25°C)	DMSO
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Zhang M, et al. Cancer Res. Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma.

[2] Zhang M, et al. Neoplasia. Trimodal glioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-β receptor I kinase inhibitor LY2109761.

[3] Melisi D, et al. Mol Cancer Ther. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis.