How 'IAP antagonist' chemicals k...(. The IAP proteins were later found in o...),Health

Date:11/15/2007

. The IAP proteins were later found in other organisms, from flies to mammals. The proteins were also shown to rise in human cancer, making them attractive targets for the development of novel cancer therapeutics. Scientists have therefore sought to design molecules that could antagonize IAPs, taking the lead from natural IAP antagonists.

Vucics group now shows that an IAP antagonist leads cIAPs to be marked for degradation by cellular components known as proteosomes. This is an amazingly rapid occurrence, happening within two minutes in cells in culture after exposure to the compound, said Vishva Dixit, who is also from Genentech.

They found that treatment with the IAP antagonist led to the activation of a NF-"B pathway that produces another protein, called tumor necrosis factor (TNFa). TNFa comes back and binds its receptor, triggering unimpeded apoptosis and killing cancer cells, Vucic said.

Likewise, Silkes team showed that synthetic and naturally occurring IAP antagonists kill susceptible tumor cells through their action on cIAP1, resulting in NF-"B activation, which drives TNFa production and initiates tumor cell death. Silke noted that the congruence between the findings of the two studies is a really good sign.

These studies show the potential for these drugs, although there is a long road to go, Silke added. It also demonstrates an important principle: If you can understand how something works through basic scientific discoveries, then you can really start to make targeted tumor therapies. We can begin to understand how tumors live and how to make them die.

Vucic said that a phase I clinical trial designed to test the safety of one of their IAP antagonist compounds in human patients is already underway.

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Contact: Cathleen Genova cgenova@cell.com 617-397-2802 Cell Press Source:Eurekalert

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