Transforming growth factor β (TGF-β) is a multifunctional protein that has been shown to possess potent growth-inhibitory activity. To identify small molecular weight compounds with TGF-β-like activities, high throughput screening was performed using mink lung epithelial cells stably transfected with a TGF-β-responsive plasminogen activator inhibitor 1 promoter/luciferase construct. Biaryl hydroxamate compounds were identified that demonstrated TGF-β-like activities. 7-[4-(4-cyanophenyl)phenoxy]- heptanohydroxamic acid (A-161906) demonstrated complete TGF-β-like agonist activity in the plasminogen activator inhibitor 1/luciferase construct. A-161906 inhibited the proliferation of multiple cell lines in a concentration-dependent manner. Cells were growth arrested at the G1-S checkpoint similar to TGF-β. Consistent with the G1-S arrest, A-161906 induced the expression of the cyclin-dependent kinase inhibitor p21waf1/cip1. A-161906 produced many cellular effects similar to that of TGF-β but did not displace labeled TGF-β from its receptors. Cells with mutations in either of the TGF-β receptors I or II were growth-arrested by A-161906. Therefore, the site of action of A-161906 appears to be distal to the receptors and possibly involved with the signaling events controlled by TGF-β.The TGF-β mimetic effect of A-161906 can be partially, if not entirely, explained by its activity as a histone deacetylase (HDAC) inhibitor. A-161906 demonstrated potent HDAC-inhibitory activity (IC50 = 9 nM). A-161906 is a novel small molecular weight compound (< 400 MW) having TGF-β mimetic activity as a result of its potent HDAC-inhibitory activity. These results and those of others demonstrate the importance of HDACs in regulation of the TGF-β signaling pathway(s). © 2002 American Association for Cancer Research.
