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...

Related Compounds

The content on this webpage is sourced from various professional data sources. If you have any questions or concerns regarding the content, please feel free to contact service1@chemsrc.com.