Platelet-derived growth factors (PDGFs) are composed of five kinds of ligand dimers, PDGF-AA, -BB, -AB, -CC, and -DD, which bind to three kinds of their receptor dimmers, PDGF receptor (PDGFR) αα, αβ, and ββ, with different affinities. PDGF and its receptors participate in various physiological processes such as embryonal development and wound healing. AG1296 potently inhibits human PDGF α- and β-receptors with IC50 of 0.3 - 0.5 μM, as well as the related stem cell factor receptor (c-Kit), but has no effect on EGFR[3]. The combination treatment of MK-2206 (5 μM) and tyrphostin AG 1296 (4 μM) for 48h induced more pronounced cell apoptosis than either MK-2206 or tyrphostin AG 1296 alone, and additive inhibition of cell migration and invasion in anaplastic thyroid carcinoma cells[4]. Consistently, intraperitoneal administration of MK-2206 (100 mg/kg) and tyrphostin AG 1296 (100 mg/kg) induced more significant inhibition characteristics on growth of KAT4 cells in nud/nud mice than either MK-2206 or tyrphostin AG 1296 alone[4]. Intraperitoneal injection of AG1296 (2 mg/kg, every other day) for 3 weeks decreased atherosclerotic plaques area in carotid arteries in ApoE-/- mice by 41.5% and inhibited inflammatory responses (49.0% and 51.8% lower in IL-6 and TNF-a, respectively)[5].
作用机制
AG1296 inhibits human PDGF α- and β-receptors by inhibiting phosphorylation of individual autophosphorylation sites of the PDGF receptor.
Tyrphostin AG1296 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Rat brain astrocytes (RBA-1 cells)
10 µM
1 hour
Inhibited JEV-induced MMP-9 expression
J Neuroinflammation. 2012 Jan 18;9:12.
Vascular smooth muscle cells
5 µM
15 min
AG1296 inhibited PDGF-stimulated PDGFR-β phosphorylation but had no effect on Ang II-induced p70 PDGFR-β phosphorylation
Biochem J. 2006 Jul 15;397(2):337-44.
IPSC-EC
20 µM, 10 µM, 5 µM
24 hours
AG1296 significantly improved cell survival under serum withdrawal and enhanced angiogenesis.
Sci Transl Med. 2021 May 5;13(592):eaba6480.
Rat brain astrocytes (RBA-1)
0.1, 1, 10 µM
24 hours
AG1296 significantly inhibited LPS-induced MMP-9 protein expression in a concentration-dependent manner
Int J Mol Sci. 2019 Dec 30;21(1):259.
Rat lung myofibroblasts
100 µM
24 hours
AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [3H]thymidine uptake
Am J Pathol. 1999 Jul;155(1):213-21.
Rat brain astrocytes (RBA-1)
10 µM
4 hours (mRNA expression) or 6 hours (promoter activity)
AG1296 inhibited LPS-induced MMP-9 mRNA expression and promoter activity
Int J Mol Sci. 2019 Dec 30;21(1):259.
A172 cells
5 µM
48 hours
Inhibited PDGFR α activity, reducing the increase in GOLM1 mRNA and protein levels
J Exp Clin Cancer Res. 2017 Dec 28;36(1):193.
Canine left atrial fibroblasts
10 µM
48 hours
AG1296 reversed PDGF-AB-induced STAT3 phosphorylation and collagen secretion
Cardiovasc Res. 2017 Mar 1;113(3):310-320.
Human lung fibroblasts (CCL-151)
10 µM
5-minute pretreatment
Inhibited PDGFR kinase activity but did not attenuate stretch-induced ERK1/2 activation
Am J Respir Cell Mol Biol. 2010 Jul;43(1):64-73.
Mouse mesangial cells
10 µM
60 minutes
Inhibited morphine- and PDGF-BB-induced MAPK/ERK phosphorylation
Br J Anaesth. 2013 Dec;111(6):1004-12.
PAH SMC
10 µM, 20 µM
AG1296 significantly suppressed the proliferation of PAH SMCs.
Sci Transl Med. 2021 May 5;13(592):eaba6480.
Mouse mammary C127 cells
50 µM
To investigate the effect of PDGF receptor tyrosine kinase inhibitor on VSOR Cl⁻ currents, results showed that AG1296 had no significant effect on VSOR Cl⁻ currents.
J Physiol. 2003 Jun 15;549(Pt 3):749-58.
Tyrphostin AG1296 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague-Dawley rats
Vanadium pentoxide-induced pulmonary fibrosis model
Intraperitoneal injection
50 mg/kg
Administered 1 hour before V2O5 instillation and again 2 days after instillation
AG1296 was more than 90% effective in preventing the increase in hydroxyproline, significantly reducing pulmonary fibrosis
Am J Pathol. 1999 Jul;155(1):213-21.
Rat
Sugen/hypoxia-induced pulmonary hypertension model
Subcutaneous injection
50 mg/kg/day
Once daily for three weeks
AG1296 significantly improved pulmonary arterial function, reduced right ventricular systolic pressure, and reversed occlusive changes in pulmonary arteries.
Sci Transl Med. 2021 May 5;13(592):eaba6480.
BALB/c mice
Allergic rhinitis murine model
Intraperitoneal injection
9 mg/kg
4 hours before each OVA inhalation, continued for 3 months
To evaluate the preventive effects of AG1296 on nasal airway remodeling in an allergic rhinitis murine model. Results showed that AG1296 significantly reduced eosinophil infiltration, suppressed MMP-9/TIMP-1 expression, and prevented subepithelial fibrosis in the nasal mucosa.
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