Patrol the border of cancer therapy in biotechnology and you're likely to find compounds based on cell-cycle checkpoints - the stopping and starting points in a cell's division - among the prospects hoping to make their way into the "promised land" of approval and marketing. The world can't get enough cancer drugs.

That tumor growth involves some abnormality in the cell-division signaling pathway hardly seems like rocket science today, but the finding in 1988 of what's known as the DNA damage checkpoint by yeast biologist Leland Hartwell earned him a Nobel Prize in 2001, and research has marched forward. Not very fast, but it has marched, with papers appearing in such journals as Nature and the Proceedings of the National Academy of Sciences.

On the industry side, the leader is ArQule Inc., which made headlines earlier this month when it parlayed the Activated Checkpoint Therapy (ACT) technology acquired in the $25 million buyout of Cyclis Pharmaceuticals Inc. into a whopper deal with Roche Holding Ltd. Under the terms, Roche is paying $15 million up front, plus research and development support described as "significant," but unspecified. The deal is focused on cancer drug candidates targeting the E2F pathway regulating cell death, and ArQule is in line for up to $276 million plus royalties from Roche, which also has an option to acquire the whole ACT program.

Not bad, considering ArQule's lead candidate is only in Phase I trials. An agreed time period during which Roche must decide whether to buy the program will be triggered partly by "us generating Phase II data in one compound and having at least one Phase I compound in the clinic," Stephen Hill, president and CEO of ArQule, told BioWorld Financial Watch.

"I can't give you specifics," said Hill, who also spoke with investors during a conference call. "It's fair to say that if Roche elects to opt in, that would precipitate a milestone payment to us that is significant."

The market has been rather disillusioned with platforms and tools, clamoring instead for products, and pharmaceutical firms are looking for later-stage opportunities. But Hill said the terms with Roche at the Phase I stage were "as good as we would have gotten" if ArQule had waited to partner until the product was more developed.

"We had a choice whether to do a deal or not, and we looked very carefully at whether we should do a deal now," he said.

"Five years ago, the difference [between deals made at Phase I compared to late Phase II or Phase III] was probably pretty dramatic, but as time goes by, fewer of those later-stage deals are available," Hill noted.

Pharmaceutical companies might want to wait until a compound or program is "de-risked," he said, "but the reality is, that's not going to provide enough of a supply." The game, then, falls to those drug companies able to recognize worthwhile opportunities early in the scientific process, "and Roche is in a good position to do that," he said. Hill was the head of global drug development at F. Hoffmann-La Roche Ltd. from 1997 to 1999.

In small-molecule approaches to cancer, ArQule lists among its competitors Ariad Pharmaceuticals Inc., Genaera Corp., Onyx Pharmaceuticals Inc., OSI Pharmaceuticals Inc., Oxigene Inc., Telik Inc. and Tularik Inc. (to be acquired by Amgen Inc. for $1.3 billion).

In checkpoint research specifically, hardly anyone else is on the radar. ArQule's chief scientific officer, Chiang Li (scientific founder of Cyclis), invented the ACT platform and worked to bring the lead compound, CO-501 - since renamed ARQ 501 - to the filing of an investigational new drug application. Li himself has published articles in more than 30 publications and holds 15 issued or filed patents.

Which is not to say that the checkpoint zone has been without encouraging news. Advances have gone well beyond the knowledge that people with genetic instability - having diseases with unnerving names such as ataxia telangiectasia, xeroderma pigmentosum, and Nijmegen breakage syndrome - also bear dangerous checkpoint defects.

Among some of the more intriguing findings have been those made by Frank McCormick, formerly with Onyx, at the University of California Cancer Research Center in San Francisco. McCormick figured out how the protein beta catenin helps colon cells evade the molecular checkpoint that would ordinary block cancer growth. McCormick and colleagues discovered that beta catenin disrupts cell regulation by synthesizing cyclin D1, a protein that spurs the cells to enter S-phase - the point at which a cell duplicates its DNA in preparation for cell division.

That was five years ago. At the first of this month, the journal Blood offered research by scientists at Virginia Commonwealth University's Medical School and Massey Cancer Center showing that checkpoint abrogator UCN-01, when combined with an experimental drug that blocks activation of Nuclear Factor-kappaB proteins that regulate cell death, might work against multiple myeloma. VCU found that exposing multiple myeloma cells to UCN-01 with the experimental agent Bay 11-7082 markedly increased cell death, including some cells resistant to steroids (often used against multiple myeloma).

All very early, putting ArQule ahead with just Phase I results and an impressive deal with Roche. The agreement goes some distance toward rebuffing the argument that mainly firms with late-stage compounds will be the ones to bag major collaborations. Scarcity has changed the picture.

"I think you'll find it's the other way around [now]," Hill said.