396129-53-6

Basic information

• Product Name: LY-364947
• Synonyms: LY-364947;[3-(Pyridin-2-yl)-4-(4-quinonyl)]-1H-pyrazole;4-[3-(2-Pyridinyl)-1H-pyrazol-4-yl]-quinoline;LY364947(HTS 466284);E 616451;HTS 466284;2-[4-(Quinolin-4-yl)-1H-pyrazol-3-yl]pyridine, 3-(Pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazole;Quinoline, 4-[3-(2-pyridinyl)-1H-pyrazol-4-yl]-
• CAS NO: 396129-53-6
• Molecular Formula: C17H12N4
• Molecular Weight: 272.31
• Product Categories: API;Inhibitors;Smad;TGF-beta
• Mol File: 396129-53-6.mol
• Article Data: 2

Chemical Properties

• Melting Point: >230℃ (dec.)
• Boiling Point: 490.8°C at 760 mmHg
• Flash Point: 268.7°C
• Appearance: white to beige/
• Density: 1.283g/cm³
• Vapor Pressure: 2.66E-09mmHg at 25°C
• Refractive Index: 1.7
• Storage Temp.: Store at RT
• Solubility: DMSO: soluble2mg/mL, clear
• PKA: 8.94±0.50(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months.
• CAS DataBase Reference: LY-364947(CAS DataBase Reference)
• NIST Chemistry Reference: LY-364947(396129-53-6)
• EPA Substance Registry System: LY-364947(396129-53-6)

Safety Data

• Hazard Codes: T,N
• Statements: 25-36/37/38-50/53
• Safety Statements: 26-45-60-61
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• Hazardous Substances Data: 396129-53-6(Hazardous Substances Data)

Usage

Description

LY-364947 is a selective ALK5 inhibitor with IC50 values of 59, 400, and 1400 nM for TGF-β RI, TGF-β RII, and MLK-7K, respectively. It is a cell-permeable compound that inhibits Smad2 phosphorylation induced by TGF-β, as well as fibronectin expression and MDA-MB-231 cell invasion. LY-364947 also abolishes the resistance of glioblastoma-initiating cells to radiation.

Uses

Used in Pharmaceutical Industry:
LY-364947 is used as a pharmaceutical compound for its ability to inhibit TGF-β signaling pathways, which play a crucial role in various cellular processes, including cell growth, differentiation, and migration. Its inhibition of Smad2 phosphorylation and cell invasion makes it a potential candidate for the development of therapeutic strategies against cancer and other TGF-β related diseases.
Used in Cancer Research:
In cancer research, LY-364947 is used as a tool to study the role of TGF-β signaling in tumor growth, invasion, and metastasis. Its ability to abolish the resistance of glioblastoma-initiating cells to radiation suggests that it may be useful in developing novel treatment strategies for glioblastoma and other cancer types.
Used in Drug Development:
LY-364947 is used in drug development as a lead compound for the design and synthesis of new ALK5 inhibitors with improved potency, selectivity, and pharmacokinetic properties. These new compounds may have potential applications in the treatment of various diseases, including cancer, fibrosis, and autoimmune disorders, by targeting the TGF-β signaling pathway.

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

InChI:InChI=1/C17H12N4/c1-2-6-15-13(5-1)12(8-10-19-15)14-11-20-21-17(14)16-7-3-4-9-18-16/h1-11H,(H,20,21)

Upstream product

• 491-35-0 C₆H₄NCH₂CHCCH₂ 
• 2459-07-6 methyl pyridine-2-carboxylate 
• 7543-22-8 2-(quinolin-4-yl)-1-(pyridin-2-yl)-ethanone 

Relevant articles and documents

NOVEL PYRAZOLE COMPOUNDS AS TRANSFORMING GROWTH FACTOR (TGF) INHIBITORS

Novel pyrazole compounds, including derivatives thereof, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use are described. The compounds of the present invention are potent inhibitors of trans