Drug, Biotech Firms Beginning To Embrace Combinatorial Chemistry

Combinatorial Chemistry An emerging chemical discovery method is proving to be a fruitful source of research and job opportunities. The technique-called combinatorial chemistry-has spawned a wave of in-house pharmaceutical research and new collaboration between drug firms and biotech companies. Similar programs may also be on the horizon for agrochemical and materials science researchers. EUREKA: Ronald Zuckerman recalls Chiron's success Combinatorial chemistry shifts compound design from a one-molecule-at-a-time approach to automated parallel synthesis. Starting with a useful compound or molecule, chemists can use robotics to spin that "lead" into thousands-or hundreds of thousands-of chemical variations. The resulting chemical diversity boosts the chance that a new compound will usefully react with a molecular target-say, a disease-causing molecule. Drug and agrochemical industry leaders predict combinatorial chemistry will speed product discovery and open new doors for chemists. Pharmaceutical companies already are retraining and hiring chemists who can understand parallel processing, perform solid-state drug synthesis, and handle huge chunks of data. Combinatorial chemistry was born about a decade ago when researchers at Affymax NV, then a start-up drug-discovery company in San Diego, first used the technique to generate libraries, or collections, of simple protein-like molecules. The approach caught fire in 1992, when researchers at the University of California, Berkeley, used it to create variants on a class of small molecules similar to the blockbuster drug Valium. Traditionally, scientists searching for new chemicals have assembled molecules one at a time in individual test tubes. Over decades, chemists have collected shelves of created compounds, which they can screen-again, one at a time-against a molecular target. It is a tedious process. "In the drug industry, combinatorial chemistry is the first thing for organic chemists to get excited about in a long time," comments David Ecker, vice president of Isis Pharmaceuticals Inc., a public company in Carlsbad, Calif. Isis soon hopes to enter clinical trials with an anti-AIDS agent discovered through combinatorial techniques. "The approach is a conceptual breakthrough that will challenge chemists," Ecker says. John Kobzina, manager of the chemistry department at Zeneca Ag Products, a Richmond, Calif.-based business unit of Zeneca Inc., agrees. Kobzina says ambitious chemists must lose the historical one-by-one image of compound design. "It's an element of getting mentally out of the box," he notes. "We need chemists unconstrained by conventional wisdom." 'NOT A PANACEA': Michael Savage is skeptical of the rapid rise. Still, some traditional compound designers are leery of combinatorial chemistry's rapid rise to fame. "It is not a panacea," cautions Michael Savage, chief executive officer of privately owned Molecular Simulations Inc., a San Diego company that creates computer software used in rational drug design. For optimal results, Savage says, combinatorial chemistry should work hand-in-hand with rational drug design and other established discovery paradigms. That is beginning to happen, he observes, adding that the combinatorial R&D revolution is probably here to stay. "The implementations will be quite heterogeneous," he forecasts. Chemists, of course, were not the first to pursue the fruits of combination. Nature was. The human body, for example, arranges 20 amino acids into countless proteins. In recent years, biologists, too, have created combination-based libraries, or collections, of DNA sequences and antibodies. For drug developers, combinatorial chemistry's promise couldn't come at a better time. Today's managed-care climate has heightened prescription drug competition. Cheap new medications win spots on a health-care buyer's formulary, or shopping list, while copycat drugs are forgotten. So companies are scrambling to create entirely new pharmaceuticals. At the same time, the Human Genome Project and other gene-hunting efforts are churning out DNA sequences for disease-related enzymes and cell receptors. Many of these molecules might ultimately generate successful drugs-if only chemists can synthesize chemicals that control them. 'A QUANTUM STEP FORWARD': Stephen Kaldor applies combinatorial principles to medicinal chemistry. The combinatorial approach is "a quantum step forward" in finding such chemicals, declares Stephen Kaldor, who heads the combinatorial chemistry effort at Eli Lilly and Co. in Indianapolis. "It makes immediate sense to apply the principles of parallel processing to medicinal chemistry," Kaldor says. Lilly currently has a combinatorial-based central nervous system drug in clinical trials. Seventy-five percent of its pre-clinical drug discovery programs also use the technique, Kaldor says. Major drug firms have been courting combinatorial companies. Lilly bought Sphinx Pharmaceuticals in Durham, N.C., for $72 million. Marion Merrell Dow Inc. acquired Tucson-based Selectide Corp. for $58 million. And in the biggest deal yet, Glaxo Wellcome Inc. purchased the original combinatorial company, Affymax, for $533 million. Other big firms, including Merck and Co. Inc. in Whitehouse Station, N.J., and Chiron Corp. of Emeryville, Calif., have launched in-house combinatorial chemistry efforts. Start-up companies also are plunging ahead, offering a dizzying array of ways to create and assay small organic molecules, which dominate the drug market. Organic chemists are at the center of the combinatorial hubbub. Using the technique, chemists typically begin with a molecule or compound known to be useful. They separate the substance into labeled fragments, often anchoring the pieces to a solid support-for example, plastic beads. Then, using automation, researchers throw in a variety of other molecular fragments. This parallel processing quickly produces a vast collection of chemicals, which are then stored. Screening the library against a drug target, chemists can go back and assay any compound or molecule that reacts with a disease target. The winning product may come as a complete surprise, as in the case of one urokinase receptor antagonist, an anticancer agent in preclinical trials at Chiron. "To begin with, we didn't know anything about what the ligand should look like," says Ronald Zuckerman, associate director of bioorganic chemistry at Chiron. "We made a diverse library with 15,000 components, selected out a reasonable candidate, and then made analogs of the candidate to find [the winner]." At major drug companies, medicinal chemists are undergoing training to acquaint them with new technology, Kaldor reports. He says simple economics motivate Lilly to retrain researchers where possible, rather than hire new expertise. "Pharmaceutical companies are not bottomless wells of money," Kaldor stresses. "We want to retrain and educate scientists internally so they can stay current and leverage the tools we find promising. So at Lilly, we make sure flexibility in adopting technologies such as combinatorial chemistry is rewarded." Job-hunting chemists may find opportunity in smaller biotech and pharmaceutical firms, which license combinatorial techniques, libraries, and targets to the giants. One hot company is newly public Pharmacopeia Inc., a drug-discovery firm in Princeton, N.J. Pharmacopeia is known for devising a type of molecular bar code for compounds, making them easy to identify within huge libraries. The company recently launched a research collaboration with Berlex Laboratories Inc., a public company in Wayne, N.J., using combinatorial techniques to pursue multiple sclerosis drug targets. Pharmacopeia also has licensed use of its combinatorial libraries and technique to Daiichi Pharmaceutical Co., a Japanese firm. Together, the two deals are worth an estimated $42 million. When it comes to a chemist, Pharmacopeia is looking for a well-trained synthetic organic chemist who thinks big, according to company president Jack Baldwin: "We need people who can think in broad terms about assay development and the overlap between biology and chemistry." NEW CHALLENGE: David Ecker notes the need for an "integrated approach." Beyond chemists, companies need combinatorial-minded molecular biologists and computational modelers, adds Ecker. "As companies figure out ways to make more molecules, they'll need to explore structural biology and computational chemistry to figure out what they've made," he says. "It's a new challenge, and it calls for an integrated approach." Integration comes in a variety of forms. Many companies use combinatorial chemistry to create libraries "biased" to include compounds with desirable properties, such as solubility or a low molecular weight. Such properties make drugs easier for the human body to accept and use. Companies are increasingly using combinatorial chemistry to optimize existing leads found via traditional medicinal chemistry, Kaldor says. "Lilly has found this is a way to build credibility for these new technologies and gain widespread acceptance within the company." One unique combinatorial tack involves biological systems. CromoXome Corp., a small San Diego start-up, is taking gene sequences from diverse microbes, pooling them, and inserting the combination into E. coli or other bacterial hosts. Their goal: to get diverse enzymes working together to produce new chemicals (K.Y. Kreeger, The Scientist, April 1, 1996, page 1). SEEKING A HIT: Michael Dickman takes a combinatorial approach with biological systems. "The top 25 drugs of 1994 were either natural products or based on them," says Michael Dickman, the company's president. "So if we find something that's a hit [binds to a drug target], there's a higher probability that you can make a drug out of it." ChromoXome plans to turn winning compounds over to drug companies, which can produce the compounds in a bacterial host and take it from there. ChromoXome has agreements with Bristol-Myers Squibb Co. of New York and San Diego-based Houghton Pharmaceuticals Inc. The company recently announced plans to double its tiny staff to 20. At this stage, no one knows how successful combinatorial biology will be, cautions Leonard Katz, a molecular biologist at Abbott Laboratories in Abbott Park, Ill. "The number of genes available that directly affect structures of pharmacological compounds are limited," Katz explains. "Thus, the diversity of structures is also limited." Katz says that if unrelated genes can yield useful hybrid compounds, combinatorial biosynthesis will catch on. Dickman is confident the approach will succeed. For individual researchers, both combinatorial biology and chemistry offer an unprecedented chance to craft diverse compounds, Dickman says: "Researchers are doing some reactions they'd never thought about doing. They can do truly interesting things." BRANCHING OUT: Peter Schultz uses combinatorial methods in material science. Combinatorial techniques have begun to catch on outside pharmaceuticals, potentially broadening the future job market for chemists. Last October, chemists at the University of California, Berkeley, reported using the method to discover a new material with important electromagnetic properties (G. Briceno et al., Science, 270:273-5, 1995). One of the researchers, Peter Schultz, founded a company called Symyx to commercialize the technology. "There are many similarities between material science and drug discovery," Schultz says. "The properties of materials are not always predictable from the structures, and synthesis is complex. So using combinatorial chemistry makes a tremendous amount of sense." Materials scientists have a "huge opportunity" to create methods that make combinatorial chemistry work, Schultz asserts. Researchers need better ways to manage arrays of materials and spot interesting chemical properties. As combinatorial chemistry matures in materials science, job opportunities will begin to open up, Schultz predicts. "With drugs, it took six years before everyone was convinced that [combinatorial methods] were the way to go," he says. GETTING OUT OF THE BOX: John Kobzina seeks chemists "unconstrained by conventional wisdom." Agricultural chemical companies also are trying out the combinatorial approach. One interested party is Zeneca. The company is producing at least 100,000 new compounds a year using combinatorial chemistry, according to Kobzina. Company officials hope a new pesticide, fungicide, or insecticide will emerge. "It's still an experiment," Kobzina says, adding that he's encouraged by initial results. PARALLEL: David Stone compares combinatorial chemistry to molecular biology. Combinatorial chemistry may crop up in other fields as well, according to David Stone, managing director of Cowen and Co., an investment banking firm in San Francisco. "It's a ubiquitous tool, much like molecular biology for biochemists," Stone says. "Researchers can just accomplish many more experiments." And when you're dealing with the whims of discovery, the more experiments you can do, the better, Baldwin points out. "The key to discovery is often the serendipity of the finding," he says. With combinatorial chemistry, researchers may find serendipity-and opportunity-is on their side. Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

Drug, Biotech Firms Beginning To Embrace Combinatorial Chemistry

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