Small Molecule TWEAK-Fn14 Inhibitors Block Cancer Growth

Drug developers have identified a series of small molecules that block the interaction of the cytokine TWEAK (TNF-related weak inducer of apoptosis) with its receptor Fn14 (fibroblast growth factor-inducible 14), which slows growth of brain, breast, pancreatic, esophageal, lung, and liver cancers.

TWEAK is a cytokine protein that belongs to the tumor necrosis factor (TNF) family and is a ligand for the Fn14/TWEAKR receptor. This cytokine has overlapping signaling functions with TNF, but displays a much wider tissue distribution. TWEAK can induce apoptosis via multiple pathways of cell death in a cell type-specific manner. This cytokine is also found to promote proliferation and migration of endothelial cells, and thus acts as a regulator of angiogenesis. Overexpression of TWEAK-Fn14 activation has been linked to tissue damage and degradation, including autoimmune diseases, as well as the survival, migration, and invasion of cancer cells.

Investigators at the Translational Genomics Research Institute (Phoenix, AZ, USA) used computer-generated protein-protein docking models to design a targeted library of small molecules predicted to disrupt the TWEAK-Fn14 interaction.

Results published in the November 8, 2013, issue of the Journal of Biological Chemistry described a group of 129 small molecules that produced up to 37% inhibition of TWEAK-Fn14 binding. Four molecules were found to be particularly potent; including compound L524-0366, which completely suppressed TWEAK-induced brain cancer-cell migration without any potential cytotoxic effects.

"Our results show that the TWEAK-Fn14 interaction is a viable drug target, and they provide the foundation for further exploration of this system in researching invasive cancers," said co-senior author Dr. Nhan Tran, associate professor of cancer and cell biology at the Translational Genomics Research Institute. "Because of its unique qualities and association with acute injuries, this drug-like molecule not only could benefit cancer patients, but also might be applied to patients with autoimmunity, heart disease like atherosclerosis, and rheumatoid arthritis."

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Translational Genomics Research Institute