It will be interesting to see what sort of advice, if any, Aaron Ciechanover has for other scientists when he picks up his Nobel Prize in chemistry today in Stockholm, Sweden.

After learning in October that he was sharing the 2004 prize with Avram Hershko and Irwin Rose, the Nobel Foundation's science reporter asked Ciechanover for his advice to young scientists. Besides suggesting to choose an important problem, Ciechanover advised, especially to scientists working with limited resources, to choose "maybe a little bit of a niche," and not work "into the mainstream, because you are doomed to lose."

Of course, Ciechanover began his Nobel Prize-wining work long ago. These days, his discovery - the ubiquitin-proteasome system for intracellular protein degradation, variously described as a cellular trash disposal or inventory control - hardly is a niche problem anymore. The ubiquitin-proteasome system is a rapidly expanding research area, and the competition is on his trail; the number of papers published on the subject has increased roughly fivefold over the past 10 years.

"Well, if I might compliment [Ciechanover], he has only himself to blame for that," Raul Rodriguez, executive vice president and chief operating officer of Rigel Pharmaceuticals, told BioWorld Today. "He did such elegant work that everyone realized this is fantastic." Rodriguez said the ubiquitin-proteasome system is "probably one of the hottest fields of academic science right now. But it's a very complicated, very subtle field."

Despite its complexities, Rodriguez said it's "very much worth investing in from a pharmaceutical standpoint." Rigel has what its executive vice president and chief scientific officer, Donald Payan, termed "probably the largest focus group" on ubiquitin in the biotechnology industry. The company's attention is focused mainly on ubiquitin ligases.

That group of 600 or so enzymes catalyzes the final step of the process that sticks ubiquitin molecules - in the unusually dramatic words of the Royal Academy when conferring the Nobel Prize, the "molecular kiss of death" - onto proteins destined for the proteasome. In the proteasome, those proteins essentially are digested into short peptides and free amino acids by three separate mechanisms: chemotryptic, tryptic and caspase cleavage. The proteasome also participates in regulating a variety of cellular pathways, including the inflammatory mediator NF-?B.

South San Francisco-based Rigel has ubiquitin-based programs in several areas, including cancer, inflammatory diseases and virology. From a scientific standpoint, the use of the ubiquitin-proteasome system in virology - specifically, to combat HIV infection - might be the most interesting. The HIV virus, among other strategies, uses its host's proteasome system against itself. HIV-infected cells normally make an antiviral enzyme, APOBEC3G, that disrupts viral replication. The virus, in turn, makes a protein known as VIF that binds to APOBEC3G, making it noticeable to ubiquitin ligase, which promptly marks it for destruction.

The virology program is at the drug discovery stage. Rigel has established assays and is screening for molecules that disrupt the binding of VIF to APOBEC3G. While it's early yet, Payan said that "targeting the host protein may give us better luck at finding a novel approach," as well as making that approach harder for the virus to work around.

Somewhat closer to the clinic is Rigel's cancer program, which again targets ubiquitin ligases. In that area, Rigel recently entered a collaboration with Merck & Co. Inc. (See BioWorld Today, Nov 16, 2004.)

From Scientific Niche To Marketed Therapeutics

Already on the market is Millennium Pharmaceuticals' Velcade (bortezomib), which works more or less as an appetite suppressant for the proteasome, inhibiting the digestion of proteins. Velcade is thought to work by inhibiting the degradation of tumor-suppressor genes; theoretically, anticancer effects of manipulating the proteasome might be achieved through decreased tumor-suppressor degradation, increased degradation of tumorigenic proteins, or tweaking the cell cycle, in whose control the proteasome is intimately involved. It is something of a brute-force approach, but has been highly successful.

Velcade first was approved in 2003 for relapsed or refractory multiple myeloma; recently, the FDA accepted a supplemental new drug application for the use of Velcade as second-line treatment in multiple myeloma, as well as granting it priority review. The review was based on results achieved in the APEX trial, a Phase III multicenter trial with 669 patients comparing Velcade to high-dose dexamethasone. Preliminary results of APEX were presented at this year's American Society of Hematology (ASH) meeting; key findings included improved survival, response rate and time to progression. Research in other indications for Velcade is ongoing, with more than 50 abstracts presented at ASH investigating Velcade's use in several hematological cancers.

Nereus Pharmaceuticals has NPI-0052 in preclinical development. The company, based in San Diego, looks for its compounds under the sea, and NPI-0052 (salinosporamide) was isolated from a marine microorganism. In vitro data presented at ASH by Nereus and Harvard Medical School's Dana-Farber Cancer Institute showed that the compound was active in multiple myeloma cells resistant to Velcade, as well as dexamethasone and doxorubicin. While the exact mechanisms still are under investigation, Nereus Chief Technical Officer Michael Palladino said that they might be due to the differential targeting of the three proteasome pathways by the two compounds.

While both Velcade and NPI-0052 are active against the chymotryptoic component of the proteasome, only NPI-0052 is active against the tryptic component, and it also might affect the caspase component of the proteasome more strongly than Velcade. Based on its in vitro and animal data, Nereus hopes to file an investigational new drug application for NPI-0052 within a year.

Given the complexity of the ubiquitin-proteasome system, most of the research still is being done at academic institutions - Rigel's Rodriguez estimated 90 percent - with biotech doing most of the rest and very little research activity to date in big pharma companies.

"The [pharma] industry, as a whole, is somewhat reluctant to dive in because of the complexity of the problem," he said. "But they are watching very carefully, and the minute it looks promising, they'll be there."

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