HSP70 Inhibitors – A Development to Watch?

Presumably a few years away, but given the institutions involved, I thought it worthwhile to post this.  While the article speaks to cancer generally, there is a note that the researchers have had success with HSP70 inhibitors in melanoma in mice.:

GSK, Penn, Wistar partnership takes on cancer, believe they've found its 'Achilles heel'

Jan 14, 2015, 12:00pm EST Updated: Jan 15, 2015, 9:08am EST

Wistar's Maureen Murphy and Penn's Donna George are working with GlaxoSmithKline on an experimental cancer treatment.

John GeorgeSenior Reporter- Philadelphia Business JournalEmail  |  Twitter  |  Google+

A trio of scientists have started working with researchers at GlaxoSmitKline on a potential cure for cancer. In fact, they believe they've found the diseases' "Achilles heel."

Last month, GlaxoSmithKline (NYSE: GSK) selected a Wistar/Penn project for its 2014 Discovery Fast Track Challenge program, which was created to accelerate the development of new medicines.

The project was submitted by: Maureen Murphy, a Wistar professor and program leader of the institute's molecular and cellular oncogenesis program; Donna George, a Penn associate professor of genetics; and Julie Leu, an assistant professor in genetics at Penn. It was the only research project involving Philadelphia-area scientists selected for GSK's two-year-old Discovery Fast Track Challenge. GSK chose 14 research project proposals for the program from 428 entries from researchers in 26 countries.

Targeting cells cancer needs to survive

The Penn/Wistar scientists are looking to develop a drug that targets a stress-induced protein, called Heat Shock Protein 70 or HSP70, that's found in low levels in normal cells, but is over-expressed in most tumor cells.

"Normal cells don't need HSP70 to survive, but cancer cells do," Murphy said. It's the Achilles heel of cancer."

The protein, Murphy explained, is linked to autophagy, which is the process through which the body in times of stress promotes survival by self-digestion. Cancer cells use the same process to survive.

"If you limit autography, normal cells will live for a time," Murphy said. "Cancer cells will die immediately.

George, Leu and Murphy discovered a series of HSP70 inhibitors that have shown to be effective against lymphoma and melanoma in mice.

They discovered the new drug candidates while studying a tumor suppressor protein known as p53. During that process, they determined that a small molecule called 2-Phenylethynesulfonamide, or PES, modified the activity of the p53 protein. They didn't know, however, what the molecule targeted to cause the modification.

To find out, George said, they had to reverse the normal drug-discovery process. Instead of identifying a target linked to a disease and developing a drug that can modify the target, the Wistar and Penn team took the more arduous route of starting with the drug candidate, but need to find the target.

"We used the drug as bait to find out what would hook onto it," George said.

The effort eventually led them to HSP70.

Murphy said they are now working with scientists in GSK Discovery Partnerships with Academia and the drug company's molecular discovery research team in the screening of their target against GSK's vast compound collection.

"We are looking for new drugs that target HSP70, and modifying our existing drug candidates to make them better," she said. "When you look at their drug screening facility, it is unbelievable. It's the size of a football field."

George said the program combines the expertise Murphy, Leu and she have with the protein, and how to target it, with the skills GSK has to rapidly test tens of thousands of compounds for a certain desired activity.

"Those are things we can't afford to do," George said. "They are not the kind of things you can do in a small lab."

Murphy said while scientists may do assays in a small number of test tubes in their lab, a pharmaceutical company like GSK will do tens of thousands of assays in a time in a "high throughput" manner with the technology they have.