Description
LY-364947 (396129-53-6) is a selective ALK5 inhibitor, IC50 = 59, 400 and 1400 nM for TGF-β RI, TGF-β RII and MLK-7K, respectively.1 Inhibits Smad2 phosphorylation induced by TGF-β as well as fibronectin expression and MDA-MB-231 cell invasion.2 LY-364947 abolishes resistance of glioblastoma-initiating cells to radiation.3?Cell permeable.
Uses
Cell permeable, potent, selective and ATP-competitive inhibitor of TGF-β RI kinase (IC50=51nM). Displays ~15-fold greater selectivity over p38α MAPK (IC50=740nM). Inhibits TGF-β-dependent cellular growth (IC50=89nM in NIH 3T3 mouse fibroblasts) and transcription activation (IC50=47nM in mink lung cells). Suppresses invasion of MDA-MB-231 breast cancer cells in a matrigel invasion assay.
Definition
ChEBI: LY 364947 is a member of the class of pyrazoles carrying pyridin-2-yl and quinolin-4-yl substituents at positions 3 and 4 respectively. It has a role as a TGFbeta receptor antagonist. It is a member of pyrazoles, a member of pyridines and a member of quinolines.
Biological Activity
Selective inhibitor of TGF- β type-I receptor (TGF- β RI, TGFR-I, T β R-I, ALK-5) (IC 50 values are 59, 400 and 1400 nM for TGR- β RI, TGF- β RII and MLK-7K respectively). Inhibits TGF- β -dependent luciferase production in mink lung cells (p3TP lux) and growth in mouse fibroblasts (NIH 3T3) (IC 50 values are 47 and 89 nM respectively). Suppresses invasion of MDA-MB-231 breast cancer cells in a matrigel invasion assay.
Biochem/physiol Actions
LY-364947 is a selective, ATP-competitive inhibitor of Transforming Growth Factor-β Type I receptor kinase (TGF-β RI, ALK5) with IC50 = 59 nM. It is much less potent at related kinases, with IC50 = 400 nM for TGF-β RII and IC50 = 1400 nM for mixed lineage kinase-7 (MLK-7), a kinase in the MAP kinase signal pathway and closely related to TGF-β RII. LY-364947 inhibits TGF-β-dependent cellular growth (IC50 = 81 nM) in NIH 3T3 mouse fibroblasts.
in vitro
ly364947 was quickly identified as a potent inhibitor (ic50= 51 nm) and was chosen as a platform for sar development. compounds were further evaluated as inhibitors of tgf-β-dependent luciferase production in mink lung cells (p3tp lux) and growth in mouse fibroblasts (nih 3t3) [1].
in vivo
in a rat model of nmda-induced retinal degeneration, simultaneous injection of nmda and the tgf-β inhibitor ly364947 slightly but significantly attenuated the reduction in number of cells in the ganglion cell layer and almost completely prevented the enhancement of capillary degeneration. [3].
References
1) Sawyer?et al. (2003),?Synthesis and activity of new aryl-and hetero-aryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain; J. Med. Chem.,?46?3953
2) Shiou?et al. (2006),?Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-beta; J. Biol. Chem.,?281?33971
3) Hardee?et al. (2012),?Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β; Cancer Res.,?72?4119
