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Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois 60064 [K. B. G., J. L., D. W. M., G. S., K. D. S., J. P., P. L., C. Z. O., S. N. A., D. J. M., C. W. W.] and Vanderbilt-Ingram Cancer Center and Department of Cancer, Vanderbilt University Medical Center, Nashville, Tennessee 37232 [M. E. A., H. L. M.]

Transforming growth factor ß (TGF-ß) is a multifunctional protein that has been shown to possess potent growth-inhibitory activity. To identify small molecular weight compounds with TGF-ß-like activities, high throughput screening was performed using mink lung epithelial cells stably transfected with a TGF-ß-responsive plasminogen activator inhibitor 1 promoter/luciferase construct. Biaryl hydroxamate compounds were identified that demonstrated TGF-ß-like activities. 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid (A-161906) demonstrated complete TGF-ß-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-ß. Consistent with the G₁-S arrest, A-161906 induced the expression of the cyclin-dependent kinase inhibitor p21^waf1/cip1. A-161906 produced many cellular effects similar to that of TGF-ß but did not displace labeled TGF-ß from its receptors. Cells with mutations in either of the TGF-ß 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-ß. The TGF-ß 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-ß 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-ß signaling pathway(s).

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