By Daniel Cressey of Nature magazine
Chaperone proteins could be the key to treating a range of diseases, including some cancers. Drugs that inhibit the function of these proteins, which help other proteins in the body to fold, are the focus of renewed research, despite the fact that for years many considered them too unorthodox a target to risk precious research dollars on.
Ten years ago, Paul Workman, director of the Cancer Therapeutics Unit at the Institute of Cancer Research in Sutton, UK, was one of only a few people pushing to develop drugs that target a chaperone protein called heat shock protein 90 (Hsp90). "There were a lot of reasons why most people thought you must be bonkers to work on Hsp90 as a target," he says. As Hsp90 assists many proteins, hitting all of those at the same time with a drug could be very toxic, people feared.
Now, there are around 20 Hsp90-targeting drugs in clinical trials around the world, and thousands of papers about Hsp90 in the literature. Next week, a session at the influential Gordon Research Conference on Medicinal Chemistry in New London, New Hampshire, will be dedicated to chaperone proteins.
Shelli McAlpine, a chaperone-protein researcher at the University of New South Wales in Sydney, Australia, who will lead the discussion at the Gordon Conference session, hopes that the conference will inspire people to look at new ways of working with chaperones.
Researchers are already talking about dealing with viruses, bacteria and infectious diseases by inhibiting chaperones. Early evidence suggests that drugs that target Hsp90 could be useful against malaria, for example.
It could also be possible to boost chaperone function to help to treat diseases thought to be related to inappropriate protein folding in the brain, such as Alzheimer's and Parkinson's.
Various chaperone proteins "are being talked about in academic papers and meetings, but Hsp90 is the proof of concept", says Workman. "What we need is to get one of these drugs approved. I think it's most likely to come from breast cancer, which is where we're getting the strongest signal from any disease."
Most cancer drugs currently in use target the hormones that cancers need to grow, says Shiuan Chen, a cancer biologist at the City of Hope cancer hospital in Duarte, California. Drug resistance can arise when the tumor starts to grow using a different molecule. But because chaperones have many 'client proteins', inactivating one chaperone should inhibit resistance by targeting not only the relevant hormone, but also its alternatives.
This is exactly what researchers are now finding. For example, at a conference last year, Chen's team presented data showing that Hsp90 inhibitors, including the next-generation compounds AUY922 and HSP990, could overcome breast cancers that are resistant to aromatase inhibitors, commonly used drugs that block synthesis of the hormone estrogen.
Back in the day
Much of the early work in this area was done on 17-allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor derived from a molecule found naturally in some bacteria. Studies showed that it could positively impact cancers, but it could cause damage to subjects' livers and was not soluble enough for easy drug delivery.
17-AAG was initially developed by Kosan Biosciences in Hayward, California, but in 2008 the company was acquired by Bristol-Myers Squib of New York, which is not currently working on the drug.
The apparent demise of 17-AAG is a source of frustration to some in the research community, because the drug showed promise in human trials. However, there are numerous other patentable small-molecule drugs in development, some of which could follow in 17-AAG's footsteps.
Workman has licensed one to Novartis of Basel, Switzerland. Named AUY922, it was developed by the Institute of Cancer Research with pharmaceutical company Vernalis, and is now going into phase II trials for breast cancer and gastric cancer.
Reducing the risk
Conventional pharmaceutical companies are abandoning whole areas of disease in an attempt to cut costs and many biotech companies have been hit hard by the financial crisis. The Hsp90 story shows how academic labs can play an important part in getting new drugs into doctors' hands.
"Drug discovery is inherently risky. Even if you have a well validated target" your project might not succeed, says Workman. "Many people, including people in industry, are saying a lot of the early risk has to be taken by academic groups, up to the point where industry has the confidence to take it on."
This cycle may soon begin again; other teams are investigating Hsp90's role in areas other than chaperoning. Jennifer Isaacs, a pharmacologist at the Medical University of South Carolina in Charleston, is working on extracellular Hsp90 (eHsp90)--Hsp90 that occurs outside of cells, where it probably has signaling functions.
This year, Isaacs's lab published a paper that suggested that eHsp90 contributes to the aggressive nature of one of the most lethal brain cancers.
"I don't think the field has yet embraced eHsp90," she says. "Probably five years from now, companies will come nosing around to buy people up."
Corrected:Workman's Hsp90 drug is AUY922, not "based on AUY922" as originally stated.
This article is reproduced with permission from the magazine Nature. The article was first published on August 2, 2011.