Small molecule antagonists of the TGF-beta1/TGF-beta receptor binding interaction.
Excessive and inappropriate action of transforming growth factor (TGF)-beta has been implicated in the pathogenesis of several disease processes, especially cancer and fibrosis. To identify antagonists of the TGF- beta 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-beta to the type II receptor (TbetaRII). About 30,000 molecules were screened resulting in the identification of five structurally related molecules that reduced binding of TGF-beta1 to soluble TbetaRII with an ED50 of approx 10 microM. The chemicals blocked inhibition of Mv1Lu cell growth by TGF-beta, TGF-beta - induced expression of luciferase driven by the TGF-beta 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-beta to its receptor and may result in novel treatment for disease.
Burmester
James K
JK
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield Clinic, Marshfield, WI 54449, USA. burmester.jim@mcrf.mfldclin.edu
Salzman
Sherry A
SA
Zhang
Kai Qi
KQ
Dart
Richard A
RA
D028341:Activins / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D028341:Activins