To figure out just what PES was doing Leu chemically tagged it to see what proteins it interacted with. They were surprised and excited to have pulled out HSP70.

Next, the team investigated the consequences of PES binding. Like many proteins, HSP70 doesn't act alone; it functions through a cadre of interacting proteins, which augment its activity. So, the team systematically scanned these proteins, to see if PES blocked their interactions with HSP70. "We found several known HSP70-interacting proteins that were no longer interacting properly when the cells were exposed to the small molecule," Leu notes.

Among those were proteins that help HSP70 refold misfolded proteins and proteins that abet its protein trafficking functions.

When they then studied the effect that loss of those functions had on the cell, the team discovered that PES blocks the cell's ability to get rid of the proteins damaged by cellular stress in a process called autophagy, a process in which cells were basically eating themselves to death. In mice, Murphy and her students Julia Pimkina and Amanda Frank found that PES could inhibit tumor formation and significantly extend survival.

"That was one of the highlights from our perspective, because PES has potential to be developed as a therapeutic," says Murphy.

PES should also be a boon to researchers trying to untangle the biology of HSP70, say the researchers. Other HSP70 inhibitors exist but they are neither generally available, nor sufficiently specific. It also provides a novel platform for anticancer therapeutics, either directly as a treatment, or as a starting point for further development.

Source: University of Pennsylvania School of Medicine