Chris Liang Blazes a Trail

By Eric Sauter

There have been a lot of firsts in Chris Liang's life, although as he explains it they were pretty much serendipitous. As a chemist at a small biotech startup in South San Francisco, he helped create the first-in-class anti-cancer kinase inhibitor. He worked on the recent collaboration with Poniard Pharmaceuticals that marked the first time that Scripps Florida outlicensed a technology developed through an industry-sponsored research agreement.

Now he has become the first Scripps Florida researcher to start his own company, Xcovery, based on next generation kinase inhibitors that target cancer and inflammatory diseases. Liang is the new company's chief science officer.

Liang was also one of the first to join Scripps Florida, arriving in 2004 as an associate professor on an invitation from Peter Schultz, a Scripps Research professor of chemistry and member of the Skaggs Institute for Chemical Biology who is based in California.

From Chemistry to Drug Discovery

Born in Hunan Province in the People's Republic of China, Liang first arrived in the United States in 1984.

"When I was in college in China, I was curious about the U.S.," he said. "At that time, we did not know much about it."

Liang came to the United States to attend graduate school at Princeton, a place he said he thought of as heaven.

"I thought Princeton was fantastic—like heaven," he said. "You have to remember that in 1984, China was behind the U.S. in nearly all aspects. When I arrived in Princeton, it was like a garden—so many trees, so many nice people."

The pleasant surprises extended to dorm living. The quarters at Princeton were spacious compared to what he was used to in China, dorms of eight students in a 200 to 300 square foot room—only two rows of bunk beds and in the middle a row of desks.

Not that the housing at Princeton convinced him to stay all that long. He graduated with his Ph.D. in four and a half years: "I studied theoretical chemistry at Princeton plus things like quantum physics, and I kept on in this theoretical vein through my first job."

Liang's first job after Princeton was with a company called Accelrys in San Diego, a small company that developed software to aid in drug discovery.

"That's how I got into drug design," he said. "Actually I developed the first software program to automate the process of binding a ligand to a protein."

Liang's career spans the computer era; he started on a UNIVAC mainframe and early Cray supercomputers, which, as he now says, had about the same computing power as the current generation of personal computers available to everybody.

"After five years, I left Accelrys to apply the software we developed to the process of drug discovery," he said. "I was also interested in how you could apply chemistry to biological systems. My supervisor at Princeton used quantum chemistry in biological systems. Though he eventually shifted his focus away from that, but the idea stuck with me."

Big Fish, Little Fish

After Accelrys, he joined Sugen, a small San Francisco biotechnology company, as a chemist, but quickly expanded his knowledge and expertise. It was also the first time he was introduced to kinases.

"Initially I had no idea what a kinase was," he said. "I got into this purely by chance because Sugen was working on finding kinase inhibitors. Of course, from the software point of view, it doesn't matter if it's a kinase or a G-protein coupled receptor. It's lucky that I got to work on kinases, rather than something like matrix metalloproteinases."

Liang spent eight years at Sugen, which was considered by many industry observers to be one of the most innovative biotech startups in the 1990s. That particular quality made the company a target for takeover and it was sold to Pharmacia. After Liang and other researchers at Sugen developed a lead compound that would eventually become the renal cell carcinoma treatment Sutent, Pharmacia was acquired by industry giant Pfizer and in true big fish-little fish form, they shut down Sugen's offices for good.

For Liang, it was the perfect time to move on.

"I had some ideas for some kinase inhibitors, so I approached Peter Schultz," Liang said. "He had offered me a place at Scripps Research earlier but I was too comfortable at Sugen. I contacted Schultz again and he said that they were looking for people and projects for Scripps Florida. I told him my ideas, and he liked them."

The Kinase Attraction

And for good reason. Kinases are highly attractive as drug compounds because they can change other proteins through the process known as phosphorylation – adding a phosphate group. In general, this addition changes the protein's function, a highly desirable trait, particularly since kinases are involved in signal transduction pathways in the cell.

Kinases are a key player in the regulation of any number of important physiological activities, including gene transcription, protein synthesis, growth factor activity, and even mitosis.

It has been estimated that as much as one third of all proteins may be susceptible to kinase modification. When kinases go bad, the signaling involved in cell growth and movement go bad as well, and that usually leads to disease, especially cancer.

As drug targets, kinases are, as one recent report from Insight Pharma suggested, "now firmly established as a major class of drug targets for the pharmaceutical industry… with the number of kinases exceeding the number of G-protein coupled receptors in the human genome."

Liang's work at Scripps Florida, where he is also director of medicinal chemistry in drug discovery, has focused on precisely those targets.

One result was the licensing to Poniard Pharmaceuticals of a class of protein kinase inhibitors for treating a variety of diseases, a successful end to a research collaboration begun in 2005.

At the time the licensing agreement was announced earlier this year, Liang said that Scripps Florida laboratory was able to accumulate data showing the kinase inhibitors in question were "very effective and selective" and showed "drug-like capabilities," which is why Poniard decided to license the molecules for further development. Liang also said that the inhibitors have shown efficacy in mouse models and had good bioavailability in an oral form.

The agreement, which gave the drug maker access to a class of compounds that have shown anti-cancer activity, marked Scripps Florida's first outlicensed technology, a milestone in the facility's relatively short history.

Liang also noted that the Poniard deal demonstrated "that although Scripps Florida is young, we have effective drug-discovery capabilities." When, in 2006, Liang established his company, Xcovery, licensing some of this technology from Scripps Research, it was another vote of confidence for the great promise of work taking place on the Florida campus.

Send comments to: mikaono[at]scripps.edu

Chris Liang's research focuses on kinases, which hold promise in drug development.