CELIA M. HENRY, C&EN WASHINGTON

Mention the biotechnology industry and most people conjure up visions of therapeutic proteins and other biologics. But the modern biotech industry does not restrict itself to proteins. The industry has evolved to include companies that use biological information to better understand their products. Now, small-molecule therapeutics, traditionally the domain of big pharmaceutical firms, are finding their way into the biotech and biopharmaceutical sectors. And with those small organic molecules comes a need for synthetic organic chemists.

	EVOLUTION At Antex Biologics, small-molecule work in antibiotics has progressed naturally from vaccine development.

The biopharmaceutical approach involves applying biological methods to understand at the molecular level how a drug works. In the early days of the pharmaceutical industry, and to a lesser extent now, many drugs were used without understanding how or why they worked. "It wasn't until the molecular biology caught up with the clinical pathology that all of a sudden this whole biopharmaceutical concept could emerge," says Gerald McMahon, senior vice president of discovery at Sugen, a biopharmaceutical company in South San Francisco. Sugen is a molecular targeting research branch of Pharmacia.

"The biotechnology industry as a whole has been very influenced by genomics and looking at large numbers of targets," says Nicholas B. Lydon, vice president for small-molecule drug discovery at Amgen in Thousand Oaks, Calif. Lydon was previously the president and chief executive officer of Kinetix, a Medford, Mass.-based biotech company that Amgen acquired this past October. "From a biotech company's perspective, you see lots of appropriate targets for small-molecule research coming down the pipeline." Lydon calls it a "natural progression" to take those targets and start developing small-molecule therapeutics.

THE BARRIERS to biotech companies entering the small-molecule arena have been greatly diminished by the advent of combinatorial chemistry and computational chemistry, Lydon says. In the past, the pharmaceutical companies' massive sample banks were considered a major advantage. "That's no longer a huge advantage when you can make and purchase diversity libraries for screening. What counts is having the right targets, the right people, and the right skills to have a successful project," he says.

In recent years, Amgen has established a small-molecule research program. "I don't think it's a change in direction, because the large-molecule approach is still what Amgen is very good at." Lydon notes. "If you look at the infrastructure that is built up on the protein-based therapeutics, it includes everything that a company would want as a toolkit for doing modern small-molecule research." Amgen's small-molecule group includes medicinal chemistry, combinatorial chemistry, high-throughput screening (both biochemistry and cell biology), and an X-ray and nuclear magnetic resonance spectroscopy group for structural determination. Lydon emphasizes that "Amgen is not going to become just a small-molecule company."

Amgen is preparing to aggressively expand its chemistry program toward the end of this year, including in the process chemistry area. The company is currently building a chemistry wing at its Thousand Oaks facility that will add approximately 100 hood spaces to its laboratories. In addition, it will be expanding into a facility in Cambridge, Mass.

Genetics Institute is another traditional biotech company with an emphasis on protein therapeutics. Two years ago, Genetics Institute was acquired by Wyeth-Ayerst. The company has started a small-molecule group, but the formation was not precipitated by the acquisition, says Robert R. Ruffolo Jr., executive vice president for research and development at Wyeth-Ayerst. "We're seeing across the board more biotechnology companies come to large pharmaceutical companies with opportunities that increasingly represent small molecules because the technology is allowing them to," he says.

Some people argue that biotech companies are more innovative than pharmaceutical companies. Ruffolo disagrees. "With the advent of genomics and every major company being involved in genomics in all therapeutic areas, I think that distinction has blurred. I would no longer accept that innovation lies with biotechnology companies," he says. He believes that the distinction between pharmaceutical and biotech companies is less relevant today than it was in the early 1990s.

Many start-up biotechnology companies have chemistry at their core. For example, Sugen pursued small-molecule therapeutics from its beginning, McMahon says. "Even though we were using a lot of the genetic engineering technology and had an appreciation of the molecular aspects of disease--in our case, cancer--we said that our products would be small synthetic molecules."

McMahon describes synthetic chemistry as "absolutely critical" to Sugen's research program. "It's the means by which we can convert interesting and potentially useful targets from the human genome into real products," he says. Sugen uses a variety of chemical approaches, including combinatorial and computational chemistry. Some projects require increasing diversity through combinatorial chemistry. Other times computational chemistry with models of target inhibition is the best approach.

"The technologies are used to different extents on different targets for different projects for different reasons," McMahon says. "There isn't a generic formula that would allow one to say that if you make 10,000 molecules you're going to end up with a blockbuster drug. It doesn't work that way."

Anadys Pharmaceuticals in San Diego and GeneSoft in South San Francisco are two other examples of biotech companies concentrating on chemistry. Richard Llewellyn, director of human resources at GeneSoft, says in the past the San Francisco Bay Area has had "a very large appetite for the biology area. Most companies are based on biology, whereas chemistry is a little newer for start-ups."

GeneSoft's scientific platform is based on small molecules originally developed by chemistry professor Peter B. Dervan of California Institute of Technology. These molecules recognize and modulate the expression of specific DNA sequences. "Right now, we're working on the diversification of our building blocks, more efficient synthesis of the final molecules, and the application of medicinal chemistry to refine our lead compounds," Llewellyn says.

The company has about 65 employees, including those in administration. The research department is split about equally between biology and chemistry, Llewellyn says. GeneSoft's chemists work closely with molecular biologists and pharmacologists to determine whether the molecules have their desired effect on gene expression and possess druglike properties.

	CENTER STAGE Chemistry plays a prominent role at Anadys Pharmaceuticals.

THE QUEST for small-molecule therapeutics has also been with Anadys from the beginning, according to Kleanthis G. Xanthopoulos, president and CEO. He says the company's vision is "to capitalize on information from the human genome sequence and other model organism sequencing efforts and use that information to translate it into small-molecule therapeutics."

Although Anadys has a focus on small molecules, it is "clearly a biotechnology company," Xanthopoulos says. "The difference with us is that we are a pioneer in understanding that and saying we're not going to be in biologics because there are already some tremendously good, very strong players there. We positioned the company exclusively on translating that new genomic information into small-molecule therapeutics."

The emphasis on small-molecule drugs gives synthetic organic chemistry a prominent role. "Genomic information cannot be really translated into therapeutics unless you put chemistry into center space," Xanthopoulos points out. "We have set chemistry, particularly synthetic organic chemistry, on center stage as the cornerstone of the platform we built, which we call high-throughput medicinal chemistry."

High-throughput coupled with medicinal chemistry might seem like an oxymoron. At Anadys, proprietary methods, in-house building blocks, and automation are used to accelerate the medicinal chemistry. "Once we have a biological activity, the next tier in the pyramid is focused medicinal chemistry, which clearly cannot be substituted with anything else," Xanthopoulos says.

Anadys has been successful in recruiting outstanding chemists because the company doesn't use chemistry as an "accessory," Xanthopoulos says. "We built the company with the focus on medicinal chemistry, not combinatorial, because we see a paradigm shift from combinatorial chemistry to information-driven medicinal chemistry." He believes that real value for Anadys is not in generating huge numbers of molecules but in rapidly designing and preparing structures based on meaningful information.

Cytokinetics, another South San Francisco start-up company, is developing small molecules that attack proteins in the cytoskeleton--that is, the proteins and microtubules that give a cell its shape. Only a few agents, such as paclitaxel, have been developed that affect the cytoskeleton, notes David J. Morgans, the company's vice president for chemistry. "Outside of academia, nobody has really done any explicit work on how to understand the majority of proteins that make up the cytoskeleton. We now have the ability to work with entirely new classes of proteins that haven't been explicitly attacked for small-molecule discovery," he says. "We want to teach the world how to do medicinal chemistry within the realm of the cytoskeleton."

Cytokinetics currently employs about 40 people in its research and development department. The ratio of biologists to chemists is about 3 to 1. Over the next 12 to 18 months, Morgans expects the department to double in size and the biologist-chemist ratio to move closer to 2 to 1. "That's probably a healthy ratio," he says. "We also outsource a lot of chemistry." For example, the company doesn't have full in-house scale-up and bioanalysis labs.

Antex Biologics, based in Gaithersburg, Md., originally focused on infectious diseases and the development of vaccines. "While we were developing vaccines, we also realized that we were identifying potential drug targets," Chairman and CEO Vic Esposito says. "We started about two years ago our own medicinal and synthetic chemistry activity, synthesizing organic molecules to be looked at as antibiotics. Our experience shows the tie-in of the use of biotechnology and medicinal or synthetic chemistry." Esposito says the demand for synthetic chemists is high at Antex and that the company is preparing to recruit several organic chemists.

SMALL COMPANIES that are starting a chemistry program tend to be biased toward synthetic organic chemists who know how to make diverse molecules. "We need people who can get in the lab, run displacement reactions, and do it without having to train them for six months," Llewellyn says. Esposito notes that it's helpful, but not required, that the chemists have an appreciation of the biology involved.

The smaller companies "don't have a lot of history with the chemistry that is the mainstay of their company," McMahon says. "Larger companies have the accumulated knowledge of chemistry that has and hasn't worked." Therefore, small companies have an even greater need than large companies for chemists who can "work from a blank sheet of paper and come up with molecules that can be useful and interesting," he says.

Chemists coming straight out of academia need a good educational background in which they've demonstrated the ability to "attack and resolve complex structures," Xanthopoulos says. For example, Anadys looks for people who have demonstrated in their graduate work the ability to solve complex synthetic problems. That young talent is then combined with an experienced medicinal chemist from industry in a mentoring relationship.

"We'll typically build teams around an experienced medicinal chemist with a group of very promising talent. We utilize a lot of internal seminars and external interactions. There are plenty of ways for promising organic synthetic chemists to enjoy their work and advance their careers as medicinal chemists at Anadys," Xanthopoulos says.

Amgen especially looks for people with industrial experience. "There's an emphasis on medicinal chemistry experience rather than just organic chemistry," he says. The company looks for people "who understand what a drug is rather than just what a molecule is. You don't find those people all the time, so we have to mix that with people straight out of good schools who have a capacity to learn," Lydon says.

THE COMPANIES WANT experienced chemists, but as McMahon points out, that experience can all be in an academic setting. "Flexibility and a little more independence are required for a smaller company because you don't have the critical mass to be able to drive projects the way a larger company can. We're always looking for chemists who are independent thinkers and creative and highly skilled," he says. "As long as we're committed to creating products that are useful for human disease and those products are small synthetics, we will always have a demand for skilled synthetic, medicinal, computational, and combinatorial chemists."

Anadys primarily hires chemists at the master's and Ph.D. levels. "Right now, we have a very high ratio of Ph.D.s to master's. If I project forward, we're likely going to continue to hire Ph.D.s, but we're probably going to be hiring chemists at all levels," Xanthopoulos says. However, he notes that a lack of an advanced degree would not exclude someone whom the company identified as talented. "If we do identify good talent at the bachelor's level, we're going to recruit them, and we will assist them in career development."

Llewellyn says that Ph.D.-level candidates are generally expected to have postdoctoral experience. "I suppose you can always find rare instances where candidates haven't done a postdoc, but hiring managers usually like to see that they have done a postdoc," he says. "In any discipline, with a postdoc you get to know more and more about a very specialized area. Usually we're looking for a pretty specific thing at that level."

Bachelor's-level chemists can be hard to find, Llewellyn says, because many people in chemistry go on to graduate school. In addition, smaller start-up companies are often reluctant to relocate people for bachelor's-level positions.

The demand for chemists in the biotech industry is expanding. However, Ruffolo points out that demand is expanding across the entire industry, including at large pharmaceutical companies. "Any kind of chemist is difficult to find. We're competing against all the other large pharmaceutical companies and biotech companies for the same pools of chemists. It's quite difficult to attract chemists."

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