LY364947

Names

[ Name ]:
LY364947

[Synonym ]:
4-[3-(2-Pyridinyl)-1H-pyrazol-4-yl]quinoline
Quinoline, 4-[3-(2-pyridinyl)-1H-pyrazol-4-yl]-
4-(5-pyridin-2-yl-1H-pyrazol-4-yl)quinoline
LY 364947
4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]quinoline
LY364947
LY-364947

Biological Activity

[Description]:

LY-364947 is a potent ATP-competitive inhibitor of TGFβR-I with IC50 of 59 nM, and exhibits 7-fold selectivity over TGFβR-II.

[Related Catalog]:

Signaling Pathways >> TGF-beta/Smad >> TGF-β Receptor

Research Areas >> Cancer

[Target]

IC50: 59 nM (TGFβR-I)

[In Vitro]

LY-364947 is an ATP competitive and tight-binding inhibitor, inhibiting phosphorylation of P-Smad3 by TGFβR-I Kinase with Ki of 28 nM. LY-364947 inhibits in vivo Smad2 phosphorylation within the NMuMg cells with IC50 of 135 nM. LY-364947 reverses TGF-β-mediated growth inhibition in NMuMg cells with IC50 of 0.218 μM. LY-364947 potentiates the xVent2-lux BMP4 response in NMuMg cells by 30% at concentrations as low as 0.25 μM. LY-364947 (2 μM) prevents TGF-β-induced epithelial−mesenchymal transition in NMuMg cells[1]. LY-364947 (3 μM) induces expression of Prox1 and LYVE-1 in almost all HDLECs after 24 hours[2]. LY-364947 promotes nuclear export of Foxo3a, with low Smad2/3 and high Akt phosphorylation levels in leukaemia-initiating cells. LY-364947 (< 20 μM) suppresses leukaemia-initiating cells colony-forming ability after co-culture with OP-9 stromal cells[3].

[In Vivo]

LY-364947 (1 mg/kg, i.p.) accelerates lymphangiogenesis, as evidence by significantly increasing the LYVE-1-positive areas in a mouse model of chronic peritonitis. LY-364947 (1 mg/kg, i.p.) significantly increases the LYVE-1-positive areas in tumor tissues in tumor xenograft models using BxPC3 pancreatic adenocarcinoma cells[2]. LY-364947 (25 mg/kg) increases p-Akt and decreases nuclear Foxo3a in leukaemia-initiating cells in CML-affected mice[3].

[Kinase Assay]

The IC50 of LY-364947 at different enzyme concentrations are determined by the filter-binding assay. Typically, 40 μL reactions in 50 mM HEPES at pH 7.5, 1 mM NaF, 200 μM pKSmad3(-3), and 50 mM ATP containing a titration of each inhibitor with concentrations of 1600, 800, 400, 200, 100, 50, 25, and 0 nM are incubated at 30°C for 30 min. The IC50 is calculated using a nonlinear regression method with GraphPad Prism software. The binding type is determined by plotting the correlation between enzyme concentrations and IC50 values.

[Animal admin]

BALB/c nude mice 5 to 6 weeks of age are used in the assay. Parental, or VEGF-C- or TGF-β1-expressing tumor cells (5×106) in 100 μL PBS are implanted subcutaneously into male nude mice and allowed to grow for 2 to 3 weeks to reach proliferative phase, before initiation of TβR-I inhibitor administration. TβR-I inhibitor LY-364947, dissolved in 5 mg/mL in DMSO and diluted with 100 μL PBS, or the vehicle control, is injected intraperitoneally at 1 mg/kg, 3 times a week for 3 weeks. Excised samples are directly frozen in dry-iced acetone for immunohistochemistry. Frozen samples are further sectioned at 10-μm thickness in a cryostat and subsequently incubated with primary and secondary antibodies. Samples are observed using a confocal microscope.

[References]

[1]. Peng SB, et al. Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry, 2005, 44(7), 2293-2304.

[2]. Oka M, et al. Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood, 2008, 111(9), 4571-4579.

[3]. Naka K, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature, 2010, 463(7281), 676-680.

[Related Small Molecules]

SB431542 | Galunisertib (LY2157299) | A 83-01 | LY2109761 | LDN193189 | RepSox | SB525334 | Vactosertib (TEW-7197) | DMH-1 | GW788388 | SB505124 | LY3200882 | H-Leu-Ser-Lys-Leu-NH2 trifluoroacetate salt | ITD-1 | K 02288

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
490.8±45.0 °C at 760 mmHg

[ Molecular Formula ]:
C₁₇H₁₂N₄

[ Molecular Weight ]:
272.304

[ Flash Point ]:
268.7±15.1 °C

[ Exact Mass ]:
272.106201

[ PSA ]:
54.46000

[ LogP ]:
2.35

[ Appearance of Characters ]:
white to beige

[ Vapour Pressure ]:
0.0±1.2 mmHg at 25°C

[ Index of Refraction ]:
1.700

[ Storage condition ]:
Store at RT

[ Water Solubility ]:
DMSO: soluble2mg/mL, clear

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS06, GHS09

[ Signal Word ]:
Danger

[ Hazard Statements ]:
H301-H315-H319-H335-H400

[ Precautionary Statements ]:
P261-P273-P301 + P310-P305 + P351 + P338

[ Personal Protective Equipment ]:
Eyeshields;Faceshields;Gloves;type P2 (EN 143) respirator cartridges

[ Hazard Codes ]:
T,N

[ Risk Phrases ]:
25-36/37/38-50/53

[ Safety Phrases ]:
26-45-60-61

[ RIDADR ]:
UN 2811 6.1/PG 3

[ HS Code ]:
2933990090

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933990090

[ Summary ]:
2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

Articles

Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.

J. Med. Chem. 46 , 3953-3956, (2003)

Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted ...

Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity versus transforming growth factor-beta type II receptor kinase and mixed lineage kinase-7.

J. Med. Chem. 49 , 2138-2142, (2006)

Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed ...

Successful shape-based virtual screening: the discovery of a potent inhibitor of the type I TGFbeta receptor kinase (TbetaRI).

Bioorg. Med. Chem. Lett. 13 , 4355-4359, (2003)

We describe the discovery, using shape-based virtual screening, of a potent, ATP site-directed inhibitor of the TbetaRI kinase, an important and novel drug target for fibrosis and cancer. The first de...