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Glaser, K.B. et al.

Glaser, Li, Aakre, Morgan, Sheppard, Stewart, Pollock, Lee, O'Connor, Anderson, Mussatto, Wegner, Moses,

Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase.

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

References

Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase. Glaser, K.B., Li, J., Aakre, M.E., Morgan, D.W., Sheppard, G., Stewart, K.D., Pollock, J., Lee, P., O'Connor, C.Z., Anderson, S.N., Mussatto, D.J., Wegner, C.W., Moses, H.L. Mol. Cancer Ther. (2002) [Pubmed]

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