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Directly activating DR5 with small moleculesAdd to my bookmarks

Nature Chemical Biology

December 24, 2012

A small molecule that induces selective cancer cell death by binding to and activating death receptor 5 (DR5) is reported this week in Nature Chemical Biology.

Tumor necrosis factor (TNF) or related molecules such as TRAIL are signaling proteins that bind to death receptors on the surface of a cell and activate cell death pathways. Several distinct stages of this cell death-promoting pathway have been targeted to induce selective cancer cell death with the aim of generating more effective cancer therapies. For example, compounds that mimic a molecule called Smac activate downstream components of this pathway. Likewise, some strategies to target the death receptors have been explored, including using TNF itself or antibodies targeted to related cell surface receptors. But these latter strategies have been hampered by the emergence of undesirable toxic side effects.

Xiaodong Wang and colleagues now report a chemical screen for small molecules that activate DR5 in synergy with Smac mimetics. This screen led the authors to discover bioymifi, a DR5 activator that induces selective cancer cell death as a single agent or in combination with Smac mimetics. They conclude that bioymifi thus represents a new strategy to directly activate DR5 in cancer cells and could have to the potential to lead to new anti-cancer therapies.

DOI:10.1038/nchembio.1153 | Original article

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