LY364947
The multifunctional cytokine transforming growth factor-β (TGF-β) is a member of a large family of growth factors involved in the regulation of a diverse array of biological processes including cell growth and differentiation, matrix modulation, and embryonic development. LY364947 is a inhibitor of the transforming growth factor-β type I receptor kinase domain.
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].
Clinical trial: Up to now, LY364947 is still in the preclinical development stage.
Reference:
[1] Sawyer JS, Anderson BD, Beight DW, Campbell RM, Jones ML, Herron DK, Lampe JW, McCowan JR, McMillen WT, Mort N, Parsons S, Smith EC, Vieth M, Weir LC, Yan L, Zhang F, Yingling JM.? 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. 2003 Sep 11;46(19):3953-6.
[2] Ueda K, Nakahara T, Mori A, Sakamoto K, Ishii K.? Protective effects of TGF-β inhibitors in a rat model of NMDA-induced retinal degeneration. Eur J Pharmacol. 2013 Jan 15;699(1-3):188-93.
- 1. Tongde Wu, Xinhua Li, et al. "Krüppel like factor 10 prevents intervertebral disc degeneration via TGF-β signaling pathway both in vitro and in vivo." J Orthop Translat. 2021 May 15;29:19-29. PMID:34094855
- 2. Meizhong Peng, Meiling Yang, et al. "Huoxin Pill inhibits isoproterenol-induced transdifferentiation and collagen synthesis in cardiac fibroblasts through the TGF-β/Smads pathway." J Ethnopharmacol. 2021 Jul 15;275:114061. PMID:33892065
- 3. Lin B, Coleman JH, et al. "Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency." Cell Stem Cell. 2017 Nov 20. pii: S1934-5909(17)30375-2. PMID:29174332
| Storage | Store at -20°C |
| M.Wt | 272.3 |
| Cas No. | 396129-53-6 |
| Formula | C17H12N4 |
| Solubility | insoluble in EtOH; insoluble in H2O; ≥24.4 mg/mL in DMSO |
| Chemical Name | 4-(5-pyridin-2-yl-1H-pyrazol-4-yl)quinoline |
| SDF | Download SDF |
| Canonical SMILES | C1=CC=C2C(=C1)C(=CC=N2)C3=C(NN=C3)C4=CC=CC=N4 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Kinase experiment [1]: | |
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Filter-binding assay |
The IC50 values of LY364947 at different enzyme concentrations were 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 were incubated at 30 °C for 30 mins. The IC50 values were calculated using a nonlinear regression method with GraphPad Prism software. The binding type was determined by plotting the correlation between enzyme concentrations and IC50 values. |
| Cell experiment [2]: | |
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Cell lines |
HOXB9-MCF10A cells |
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Preparation method |
The solubility of this compound in DMSO is limited. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
10 μM; 24 hrs |
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Applications |
In HOXB9-MCF10A cells, LY364947 suppressed Smad2 phosphorylation by inhibiting TGF-β activation, meanwhile, without affecting the expression of TGF-β1 and TGF-β2. Besides, LY364947 induced epithelial morphological changes, with re-expression of E-cadherin as well as suppression of fibronectin and vimentin. In addition, LY364947 reduced migration and invasiveness of HOXB9-MCF10A cells. |
| Animal experiment [3]: | |
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Animal models |
A rat model of NMDA-induced retinal degeneration |
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Dosage form |
50 nM; 5μL; intravitreal injection |
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Applications |
In a rat model of NMDA-induced retinal degeneration, LY364947 significantly suppressed cell loss in the ganglion cell layer induced by NMDA. Besides, LY364947 markedly prevent vascular damage in the injured retina caused by NMDA. In addition, co-treatment with NMDA and LY364947 did not cause any morphological change of NG2-positive pericytes. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Peng SB, Yan L, Xia X, Watkins SA, Brooks HB, Beight D, Herron DK, Jones ML, Lampe JW, McMillen WT, Mort N, Sawyer JS, Yingling JM. Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry. 2005 Feb 22;44(7):2293-304. [2]. Hayashida T, Takahashi F, Chiba N, Brachtel E, Takahashi M, Godin-Heymann N, Gross KW, Vivanco Md, Wijendran V, Shioda T, Sgroi D, Donahoe PK, Maheswaran S. HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1100-5. [3]. Ueda K, Nakahara T, Mori A, Sakamoto K, Ishii K. Protective effects of TGF-β inhibitors in a rat model of NMDA-induced retinal degeneration. Eur J Pharmacol. 2013 Jan 15;699(1-3):188-93. |
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Quality Control & MSDS
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