Smac-ing back at cancer cells( the target protein IAP said Wang. We...)

According to HHMI investigator Steven F. Dowdy, who co-authored a Perspectives article in Science, the key to the study is that Wang and his colleagues took advantage of the fact that the Smac-IAP protein-protein interaction is relatively unstructured, since only the N-terminal amino acids of Smac interact with IAP.

"This property allowed them to readily create a library of non-natural amino acids and search for one that looked like the Smac N-terminal domain and fit into the groove of IAP that triggers it to unleash caspases. And they found one that responds nearly identically in terms of concentration, but it's resistant to proteases and it can penetrate the cell membrane just like other small molecules," said Dowdy, who is at the University of California, San Diego School of Medicine. The result of the search for Smac mimics was a molecule the researchers called "Compound 3."

"The way we arrived at Compound 3 was serendipitous," said Wang. "At first we thought that just mimicking the last four amino acids of Smac was the way to go, but we weren't getting anywhere. But in one of the chemical reactions, we actually made a dimer linking the molecules in pairs. That dimer, Compound 3, turned out to be much more active." The scientists believe the twinned molecule is more active because the Smac protein itself is a combination of two identical proteins, although the reason for Compound 3's activity remains unclear.

Compound 3's striking apoptosis-triggering activity revealed itself when the scientists introduced it into cultures of human glioblastoma cells. "We picked human glioblastoma because it is the hardest to kill," said Wang. "The cells grow like weeds and they are tough as a rock."

The cells, however, were no match for Compound 3. When the researchers a
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
8-Sep-2004