Transforming Growth Factor β Mimetics: Discovery of 7-[4-(4-Cyanophenyl) phenoxy]-Heptanohydroxamic Acid, a Biaryl Hydroxamate Inhibitor of Histone Deacetylase

• Published in: Molecular cancer therapeutics Vol. 1; no. 10; p. 759
• Main Authors: Glaser, Keith B, Li, Junling, Aakre, Mary E, Morgan, Douglas W, Sheppard, George, Stewart, Kent D, Pollock, Jennifer, Lee, Paul, O'Connor, Chad Z, Anderson, Steven N, Mussatto, Donna J, Wegner, Craig W, Moses, Harold L
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.08.2002
• Subjects: Acetylation; Animals; Biphenyl Compounds - pharmacology; Blotting, Western; Cell Cycle; Cell Division; Cell Line; Collagenases - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Epithelial Cells - metabolism; Fibroblasts - metabolism; Fibronectins - biosynthesis; G1 Phase; Gelsolin - metabolism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids - pharmacology; Inhibitory Concentration 50; Keratinocytes - metabolism; Luciferases - metabolism; Lung - cytology; Mice; Mink; Models, Chemical; Phenotype; Plasminogen Activator Inhibitor 1 - genetics; Promoter Regions, Genetic; S Phase; Time Factors; Transfection; Transforming Growth Factor beta - chemistry; Transforming Growth Factor beta - pharmacology
• ISSN: 1535-7163; 1538-8514

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 G 1 -S checkpoint similar to TGF-β. Consistent with the G 1 -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-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 (IC 50 = 9 n m ). 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).