SD-208 is a potent, orally active ATP-competitive transforming growth factor-β receptor 1 (TGF-βRI) inhibitor (IC50= 49 nM) and displays > 100-fold and > 17-fold selectivity over TGF-βRII and other common kinases respectively.
The TGF-β pathway regulates a wide variety of cellular processes in many different cell types and biological contexts. There are three identified TGF receptor ligands, TGF-β1, 2 and 3. Activated TGF-β ligands can interact with TGF-β type II receptors (TβRII), then recruit and phosphorylate the TGF-β type I receptors (also called as TβRI or ALK5). In turn, activated TβRI phosphorylates SMAD2 and SMAD3 at C-terminal serine residues. Following that, phosphorylated SMAD and SMAD3 assemble into heterodimeric and trimeric complexes with SMAD4. Then the trimeric complex translocates into the nucleus and regulates the expression of TGF-β target genes[2]. SD-208 is a selective inhibitor of TGF-βR1 with IC50 value of 48nM, 100-fold compared with TGF-βRII kinase (measured by cell-free kinase activity). Pre-exposure to 1uM SD-208 for 24h can abolish the p-Smad2 induced by 1-hour treatment of endogenous TGF-β or exogenous TGF-β (5ng/ml) in SMA-560 or LN-308 glioma cells. Decreased activity of TGF-β reporter, pGL2 3TP-Luc or pGL3 SBE-2 Luc reporter, can be observed in the presence of SD-208 at 0.1 or 1uM in the cells exposure to TGF-β (5ng/ml) for 16h. These results indicated the abrogation of TGF-β signaling by SD-208. SD-208, at 1uM for 24h, did not show direct cytotoxicity but can inhibit the migration and invasion of SMA-560 cells evoked by TGF-β (5ng/ml). Also, in vitro study showed SD-208 can enhance allogeneic immune responses to glioma cells. Orally administered SD-208 on dose of 30, 90 and 120mg/kg can inhibit TGF-β–dependent phosphorylation of Smad2/3 in brain of SMA-560 intracranial experimental glioma-bearing syngeneic mice, as well as prolonged the survival of the mice[1]. SD-208 at concentration of 30-300nM for 48h can abrogate IL-6 and VEGF secretion from BMSCs cultured with MM cells, as well as SD-208 abrogates IL-6 and VEGF secretion from BMSCs cultured with MM cells, which showed the regulation activity of SD-208 on MM cells in the bone marrow microenvironment[3]. Inhibition of TGF-β signaling by SD-208 can inhibit the induction of fibrosis and block progressive fibrosis in pulmonary fibrosis rat models[4].
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