Small molecule antagonists of the TGF-β1/TGF-β receptor binding interaction

Authors: Burmester, James¹; Salzman, Sherry²; Zhang, Kai²; Dart, Richard³

Source: Medical Oncology, Volume 23, Number 4, December 2006 , pp. 553-562(10)

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Abstract:

Excessive and inappropriate action of transforming growth factor (TGF)-β has been implicated in the pathogenesis of several disease processes, especially cancer and fibrosis. To identify antagonists of the TGF-β ligand-binding domain that may have therapeutic potential, we screened the National Cancer Institute open access chemical repository for molecules that inhibited binding of TGF-β to the type II receptor (TβRII). About 30,000 molecules were screened resulting in the identification of five structurally related molecules that reduced binding of TGF-β1 to soluble TβRII with an ED50 of approx 10 μM. The chemicals blocked inhibition of Mv1Lu cell growth by TGF-β, TGF-β-induced expression of luciferase driven by the TGF-β response element, and induction of plasminogen inhibitor mRNA detected by Northern blot. In contrast, the chemicals did not block activin-induced inhibition of cell growth. Our results identify a novel chemical group that blocks binding of TGF-β to its receptor and may result in novel treatment for disease.

Keywords: Cancer; fibrotic disease; growth inhibition; ligand interaction; molecular screening

Document Type: Research article

DOI: http://dx.doi.org/10.1385/MO:23:4:553

Affiliations: 1: Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, 54449, Marshfield, WI, USA, Email: burmester.jim@mcrf.mfldclin.edu 2: Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, 54449, Marshfield, WI, USA, 3: Department of Nephrology, Marshfield Clinic, Marshfield, Wisconsin, USA,

Publication date: 2006-12-01