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.3Cell permeable.
Uses
LY 364947, is a potent ATP-competitive inhibitor of Tgf-b signaling.
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].
Background
LY-364947, also known as HTS-466284, is a potent and selective TGF-β type-I receptor inhibitor. This small molecule specifically targets TGF-β RI with an IC50 value of 59 nM and is less effective on TGF-β RII and MLK-7K. LY-364947 regulates MDA-MB-231 cell invasion by inhibiting autocrine TGF-β signaling. Patients in intensive care units that suffer from chronic sepsis can experience weakening of the diaphragm muscles caused by muscle wasting, requiring mechanical ventilation. Members of the TGF-β family can trigger the activation of protein breakdown. Inhibition of the TGF-β pathway can protect the diaphragm during chronic sepsis, making LY-364947 an interesting compound to study as it relates to effective ICU patient care.
References
[1] J. SCOTT SAWYER. Synthesis and Activity of New Aryl- and Heteroaryl-Substituted Pyrazole Inhibitors of the Transforming Growth Factor-β Type I Receptor Kinase Domain[J]. Journal of Medicinal Chemistry, 2003, 46 19: 3953-3956. DOI:
10.1021/jm0205705[2] SHENG-RU SHIOU. Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-beta.[J]. The Journal of Biological Chemistry, 2006, 281 45: 33971-33981. DOI:
10.1074/jbc.m607010200[3] MATTHEW E HARDEE. Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β.[J]. Cancer research, 2012, 72 16: 4119-4129. DOI:
10.1158/0008-5472.can-12-0546
