AG 1296 is an inhibitor ofPDGFR with IC50 of 0.3-0.5 μM, no activity to EGFR. It also inhibitsFGFR andc-Kit with IC50 of 12.3 μM and 1.8 μM in Swiss 3T3 cells.
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.
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