LY-364947 is a selective, ATP-competitive inhibitor of Transforming Growth Factor-β Type I receptor kinase. LY364947 inhibits TGF-β-dependent luciferase production in mink lung cells (p3TP lux) and growth in mouse fibroblasts (NIH 3T3) (IC50 values are 47 and 89 nM respectively). LY364947 is much less potent at related kinases, with IC50 of 400 nM for TGF-β RII and IC50 of 1400 nM for mixed lineage kinase-7 (MLK-7), a kinase in the MAP kinase signal pathway and closely related to TGF-β RII. LY364947 (3 μM) induces expression of Prox1 and LYVE-1 in almost all HDLECs after 24 hours. LY364947 (25 mg/kg) increases p-Akt and decreases nuclear Foxo3a in leukaemia-initiating cells in CML-affected mice.
|Source||Cancer Res (2012). Figure 1. LY364947|
|Cell Lines||radiosensitizes glioma cells|
|Incubation Time||24 h|
|Results||Regardless of TGFβ-mediated growth modulation, addition of the TGFβ inhibitor LY364947 significantly increased the radiosensitivity of all three cell lines as measured in clonogenic assay|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo.
Bouquet F, et al. Clin Cancer Res. 2011 Nov 1;17(21):6754-65. PMID: 22028490.
The specificities of small molecule inhibitors of the TGFß and BMP pathways.
Vogt J, et al. Cell Signal. 2011 Nov;23(11):1831-42. PMID: 21740966.
Smad4 regulates claudin-1 expression in a transforming growth factor-beta-independent manner in colon cancer cells.
Shiou SR, et al. Cancer Res. 2007 Feb 15;67(4):1571-9. PMID: 17308096.
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