Description
Protein tyrosine kinase (PTK) inhibitors are potential antiproliferative agents for diseases caused by the hyperactivity of PTKs. Tyrphostins are a class of antiproliferative compounds which act as PTK blockers. PTK inhibitors specific for platelet-derived growth factor (PDGF) receptor kinase could help in the treatment of atherosclerosis, restenosis, pulmonary fibrosis, and gliomas. AG-1295 is a quinoxaline-type tyrphostin that acts as a potent and selective inhibitor of PDGF receptor kinase in vitro and in Swiss 3T3 cells (IC50s range from 0.3-1 μM). It inhibits PDGF-stimulated DNA synthesis with an IC50 value of 2.5 μM without affecting activity of the EGF receptor.
Uses
AG-1295 is a protein tyrosine kinase inhibitor. Antiproliferative agent used in the treatment of atherosclerosis, pulmonary fibrosis, and gliomas.
Definition
ChEBI: 6,7-dimethyl-2-phenylquinoxaline is a quinoxaline derivative. It has a role as a geroprotector.
in vitro
the previous study investigated the effect of pdgf receptor-beta (pdgfr-β) inhibition by ag-1295 on the osteogenic differentiation of the mouse pre-osteoblastic cell line mc3t3-e1. results showed that ag-1295 could significantly increase the alkaline phosphatase (alp) activity and enhance the formation of mineralized nodules dose-dependently. moreover, the treatment with ag-1295 led to the up-regulated mrna expression of the osteogenic marker genes collagen type i, runt-related transcription factor 2, osterix, tissue-nonspecific alkaline phosphatase, as well as osteocalcin. consistent with its effect on osteoblast differentiation, ag-1295 was also able to significantly suppress the phosphorylation of erk1/2 in mc3t3-e1 cells [1].
in vivo
a previous animal study was designed to evaluated the possible effects of ag1295 on the development of interstitial fibrosis in rats with unilateral ureteral obstruction, monitored by ed-a+ fibronectin expression, the number of macrophages. results showed that the i.p.treatment with ag1295 at 12 mg/kg could significantly reduce interstitial fibrosis as verified by a smaller sirius-red stained area and also by a reduced number of macrophages, and by the ed-a+ fibronectin deposition and the number of cells positive for α-smooth muscle actin [2].
IC 50
0.3-1 μm for pdgf receptor kinase in vitro and in swiss 3t3 cells
References
[1] zhang yy, cui yz, luan j, zhou xy, zhang gl, han jx. platelet-derived growth factor receptor kinase inhibitor ag-1295 promotes osteoblast differentiation in mc3t3-e1 cells via the erk pathway. biosci trends. 2012 jun;6(3):130-5.
[2] ludewig d, kosmehl h, sommer m, bhmer fd, stein g. pdgf receptor kinase blocker ag1295 attenuates interstitial fibrosis in rat kidney after unilateral obstruction. cell tissue res. 2000 jan;299(1):97-103.
