COMBINATORIAL CHEMISTRY - C&EN Global Enterprise (ACS

SPECIAL REPORT

COMBINATORIAL r'IJTIG'MÏSTlIV

hemistry, being a highly creative discipline, generates innovative new ideas constantly. Over time, these ideas are incorporated into the corpus of the science, and often subsequently into the technology that drives the chemical enterprise. Sometimes, though, a new idea has such innovative force that it sweeps through the discipline like a fast-moving brushfire through dry chaparral. Such is the case with combinatorial chemistry, a term that describes a set of tools for generating vast chemical diversity rapidly and efficiently. Combinatorial chemistry has captured the collective imagination of the medicinal chemistry community because of its potential for revolutionizing drug discovery. Combinatorial chemistry doesn't actually change the drug discovery process, which by necessity involves the screening of large numbers of compounds for potential biological activity. Rather, it introduces a new step, one that greatly increases the range of molecular diversity available to medicinal chemistry. This is done, at least in part, by accepting and harnessing randomness in the synthesis of molecules. The trick is to tame the randomness by creative techniques that allow the medicinal chemist to fish out from a mixture of compounds those that point to drug leads. The first article in C&EN on a combinatorial approach to chemical synthesis appeared in the Feb. 25,1991, issue. No-

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FEBRUARY 12,1996 C&EN

The drug discovery process is being reshaped by a method that rapidly and efficiently makes huge numbers of molecules available for screening as drug leads where in that article, however, do the terms "combinatorial chemistry" or "combinatorial synthesis" appear. The term "combinatorial synthesis" appeared in C&EN for the first time in the Jan. 18, 1993, issue in an article describing the work of Jonathan A. Ellman and coworkers at the University of California, Berkeley, on synthesis of a library of 1,4-benzodiazepines. Through 1993, an increasing number of papers on combinatorial approaches to synthesis from an increasing number of independent research groups appeared in the literature, and C&EN's Feb. 7, 1994, cover story was a major wrapup on the field. As the following three-part Special

Report makes clear, the pace of research on combinatorial chemistry, as well as its development as a business in its own right, has continued to quicken over the past two years. Medicinal chemists have made major strides toward improving the synthetic strategies used to generate libraries of compounds, particularly the small organic compounds that are the most promising drug candidates. They have also dramatically refined approaches to labeling compounds synthesized combinatorially so that they can be efficiently screened for biological activity and subsequently identified. The business side of the equation also has evolved. Many of the small entrepreneurial companies that sprang up to exploit combinatorial chemistry have entered into partnerships with major drug firms that desire access to this new technology. The big drug companies have also set up in-house research programs to exploit combinatorial chemistry. Another side of the business equation has also manifested itself as information management and computational chemistry specialists produce software to deal with the huge volume of data combinatorial chemistry generates. Truly, this fledgling subdiscipline of medicinal chemistry, only a gleam in the eyes of a few entrepreneurs and academic researchers five years ago, has caught fire. Rudy Baum

Combinatorial chemists focus on small molecules, molecular recognition, and automation

ing combinatorial chemistry with computational drug-design strategies to the use of combinatorial molecular recognition for studies of protein function.

Stu Borman, C&EN Washington

Creating libraries

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rug candidates traditionally have been synthesized one at a time, a time-consuming and labor-intensive process. But many researchers in academia, government, biotechnology firms, and drug companies increasingly are turning to combinatorial chemistry—a strategy for creating new drugs that, it is hoped, will speed the drug discovery process significantly. The idea of combinatorial chemistry is to make a large number of chemical variants all at one time; to test them for bioactivity, binding with a target, or other desired properties; and then to isolate and identify the most promising compounds for further development. The success of combinatorial chemistry is still uncertain. No drugs discovered combinatorially have been approved for marketing, although several are currently in development. But many researchers believe the technique will prove to be an efficient and cost-effective tool for identifying new medicines. In combinatorial chemistry experiments, chemical libraries (large collections of compounds of varied structure) are produced by sequentially linking different molecular building blocks, or by adding substituent "decorations" to a core structure such as a poly cyclic compound. Libraries may consist of molecules free in solution, linked to solid particles or beads, or even arrayed on surfaces of modified microorganisms. Combinatorial chemistry initially focused on the synthesis of very large libraries of biological oligomers such as peptides and oligonucleotides. But drug developers generally prefer to focus on small organic molecules with molecular weights of about 500 daltons or less—the class of compounds from which most successful drugs have traditionally emerged. So combinatorial chemistry researchers are concentrating on small organic compounds as well. Drug discovery is the primary goal of most combinatorial chemistry research, but combinatorial methods also have

potential applications for development of advanced materials and catalysts. One of the challenges of combinatorial chemistry is the difficulty of identifying "hits" (active compounds) present at vanishingly low concentrations in complex combinatorial libraries. To address this problem, ingenious encoding schemes have been developed. Two groups have independently developed the latest concept in this field—radiofrequency encoding, in which information about library compounds is stored on microchips. Instrumentation systems to help

speed combinatorial chemistry experiments have been developed in-house at a number of biotechnology and pharmaceutical companies. And several combinatorial automation systems are available commercially or undergoing intensive development. Combinatorial chemistry has come a long way in just a few years, but further advances are needed and new applications are anticipated. Directions in which the field is headed range from combin-

ACSIII PUBS Combinatorial Chemistry is available on the World Wide Web at http://pubs.acs.org. Click on "What's New" or "Hot Articles."

Combinatorial libraries are created in the laboratory by one of two methods— split synthesis or parallel synthesis. In split synthesis, compounds are assembled on the surfaces of microparticles or beads. In each step, beads from previous steps are partitioned into several groups and a new building block is added. The different groups of beads are then recombined and separated once again to form new groups. The next building block is added, and the process continues until the desired combinatorial library has been assembled. Before split synthesis was developed, explains chemistry professor Kim D. Janda of Scripps Research Institute, La Jolla, Calif., "people created diversity using mixtures of compounds. In a coupling step, you would add, lef s say, reagents A, B, and C in one pot, and A, B, and C would all compete to become integrated at the same site. But in doing that you can have problems with kinetics. One reaction may be faster than another and you may not get equal distribution of the three components." Split synthesis "got away from all that," says Janda. "You could create diversity using separate reactions, so the components would have an equal chance to add in to a site, and then by mixing compounds together again you got the diversity you needed." Libraries resulting from split synthesis are characterized by the phrase "one bead, one compound." Each bead in the library holds multiple copies of a single library member. Split synthesis greatly simplifies the isolation and identification of active agents because beads (and implicitly individual library members) are large enough to be observed visually and separated mechanically. Combinatorial libraries can also be made by parallel synthesis, in which different compounds are synthesized in separate vessels (without remixing), often in an automated fashion. Unlike split synthesis, which requires a solid support, parallel synthesis can be done either on a solid support or in solution. A commonly used format for parallel FEBRUARY 12,1996 C&EN

29

SPECIAL REPORT

USA, 92, 6419 (1995)]. The prosynthesis is the 96-well micedure involves use of polyethcrotiter plate. Robotics instruSplit synthesis yields one library ylene glycol monomethyl ether mentation can be used to add member per bead in place of solid-phase beads as different reagents to separate a foundation for combinatorial wells of a microtiter plate in Three types of assembly. The polymer is solua predefined manner to pro>% monomers are Beadble in a variety of aqueous and duce combinatorial libraries. coupled to beads L organic solvents, making it Hits from the library can Combine possible to use solution-phase then be identified by well combinatorial synthesis. But location. 6 m b I the polymer can be precipitatSplit synthesis is used to b ®-o -o ed out of solution by crystalliproduce small quantities of a Divide zation at each stage of the comrelatively large number of binatorial process to facilitate compounds, whereas parallel J> • purifications. synthesis yields larger quantities of a relatively small numSmall-molecule libraries Couple ber of compounds. And split synthesis requires that assays Combinatorial chemistry be performed on pools of combegan with the synthesis of Nine dimers > pounds, whereas assays on inlarge libraries of biopolymers dividual compounds can be such as peptides and oligonucleotides. In some cases, these run on libraries created by parCombine, were created on surfaces of allel synthesis. While slower, -j divide, and T couple genetically modified microtesting individual compounds organisms, such as bacteriois sometimes advantageous ©V phage particles, by inserting because serious interferences combinatorial DNA oligomers and complications can arise ex* ' • Twentyinto genes that encode cellwhen multiple compounds are seven trimers p surface proteins. tested simultaneously. ^ v r b®^~®^ However, peptides and oliA special case of parallel gonucleotides are problematic synthesis is spatially addressfor drug development beable synthesis, pioneered by r e searchers at Affymax Research Institute, since excess reagents can be washed away cause their oral bioavailability is poor Palo Alto, Calif. In this technique, librar- from beads very easily afterward. How- and they are degraded rapidly by enies are synthesized in arrays on micro- ever, solution-phase synthesis is more zymes. Hence, the focus of combinatochips, and all the compounds on a chip versatile because many organic solution- rial research has shifted in recent years are assayed simultaneously for binding based reactions have not been adapted for to libraries of nonpolymeric small molecules having molecular weights of or activity. Hits can then be identified by solid-phase work. the piece of real estate they occupy on Janda and coworkers at Scripps re- about 500 daltons or less. In a pioneering study, chemistry the chip. Using a chip-making technique cently developed a liquid-phase synthecalled photolithography, Affymax re- sis procedure that combines some of the professor Jonathan A. Ellman and cosearchers have generated arrays of more advantages of solution-phase and solid- workers at the University of California, than 65,000 compounds on chips about phase synthesis [Proc. Natl. Acad. Sci. Berkeley, synthesized the first such library by creating variants 1 sq cm in area. of benzodiazepines, a class Bioactive combinatorial of compounds that has compounds synthesized by Spatially addressable synthesis produces been a fertile source of sucsplit synthesis can also be one library member per site cessful drugs [/. Am. Chem. identified by deconvolution, Soc, 114,10997 (1992)]. Since a technique in which each then, researchers have found T • variable position in a comways to synthesize combinapound library is tested to • • • torial libraries based on find the building block that many other classes of small makes the strongest contri• • • organic compounds. bution to activity at that • • • A recent example is work site. • • • by Mark A. Gallop, director Solid-phase and solutionof combinatorial chemistry, phase combinatorial syntheand coworkers at Affymax. sis each have their advantagThey used a cycloaddition "Orthogonal stripe" method is one of many different es and disadvantages. Solidmasking strategies that can be used for spatially addressreaction to prepare a smallphase synthesis permits use able synthesis. molecule combinatorial liof excesses of reagents to brary of about 500 mercapdrive reactions to completion,

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toacyl prolines [/. Am. Chem. Soc, 117, 7029 (1995)]. By screening this library, they identified an unusually potent inhibitor of angiotensin-converting enzyme (ACE). ACE inhibitors are used as treatments for hypertension and heart disease. And the group of Stephen W. Kaldor, head of combinatorial chemistry research at Eli Lilly & Co., Indianapolis, in collaboration with scientists in Lilly's central nervous system (CNS) group, has used combinatorial chemistry to identify an orally active CNS agent by combinatorial optimization of an existing lead. The low molecular weight nonoligomeric drug candidate entered clinical trials in November. 'This is one of the first small-molecule combinatorial compounds to go into humans," says Kaldor. A major challenge of small-molecule combinatorial chemistry has been to adapt conventional solution-phase organic reactions to reactions on solidphase particles. Ellman says one of his group's efforts "has been to expand the

Benzodiazepines and mercaptoacyl prolines form representative small-molecule libraries

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smaller mixtures—probably a hundred components or less in a mixture, rather than the mixtures of 105 and 106 compounds per pool that we saw in the early experiments," says Ronald N. Zuckermann, associate director of bioorganic chemistry at Chiron Corp., Emeryville, Calif. 'The lower the number of compounds, the more confidence you can have in the biological data" because artifacts arise more readily in the screening of large pools of compounds. Ellman agrees that "people have gotten away from screening really large mixtures of compounds. They either want to screen them individually or in smaller pools of under 100 compounds. If s easier to extract out binding data in that format."

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Oligomers and materials Carbohydrates have lagged behind other types of compounds in combinato- ing pursued combinatorially is peprial library development because of the toids, peptide analogs that are not reccomplexity of oligosaccharide chemistry, ognized by peptide-cleaving enzymes. but carbohydrate libraries are now be- Chiron researchers recently discovginning to appear. For example, Ole ered a candidate urokinase receptor Hindsgaul and coworkers at the depart- antagonist from a peptoid library, and ment of chemistry of the University of the compound is currently in precliniAlberta, Edmonton, in collaboration cal studies as a potential anticancer with researchers at the University of agent. Georgia, Athens, and Ciba Central Re"One of the primary advantages of search Laboratories, Basel, Switzerland, peptoids is their synthetic accessibilihave developed a "random glycosyla- ty," says Zuckermann. "They are effition" strategy for making oligosaccha- ciently synthesized by the submonoride libraries in solution [Angew. Chem. mer method, which uses primary Int. Ed. Engl 34, 2720 (1995)]. They pro- amines and bromoacetic acid as startduced a library of all 18 possible fucosylated trisaccharides from disaccharide precursors. Memory chips can encode libraries And at a recent meeting, chemistry professor Daniel E. Kahne of Memory Princeton University reported conchip struction of the first solid-phase carbohydrate library, using chemistry for solid-phase synthesis of oligosaccharides developed earlier by his group. This technique has been licensed to Transcell Technologies, Monmouth Junction, N.J. In preliminary work, compounds isolated from one carbohydrate library have been shown to bind a carbohydratebinding protein with greater affinity than the protein's natural liPorous shell Beads (solid gand. "Carbohydrates play a cenof spherical supports for capsule tral role in some very important combinatorial synthesis) biological processes, so having access to libraries of these comSource: IRORI Quantum Microchemistry pounds is critical," says Kahne. Another type of oligomer be34


ing materials—both very cheap, and there are literally thousands of amines readily available. The combination of this chemistry with robotic synthesis has led to a truly high throughput synthesis facility." Chiron's identification of nanomolar peptoids that bind to transmembrane receptors [/. Med. Chem., 37, 2678 (1994)] "was the first example of the discovery of potent ligands to pharmaceutically relevant receptors from a combinatorial library of nonpeptides or nonnucleic acids—that is, synthetic compounds/' Zuckermann adds. "I believe that this work helped inspire others to continue to move away from peptides and further toward small molecules/' Combinatorial chemistry can also be extended entirely beyond the realm of organic chemistry. For example, physicist Xiao-Dong Xiang of Lawrence Berkeley National Laboratory, chemistry professor Peter G. Schultz of UC Berkeley, and coworkers recently devised a combinatorial strategy for finding advanced materials with novel chemical or physical properties— extending "the combinatorial approach from biological and organic molecules to the remainder of the periodic table," as they put it {Science, 268,1738 (1995)]. Xiang, Schultz, and coworkers used thin-film deposition and physical masking techniques to synthesize libraries of solid-state materials. The properties of the resulting materials were then evaluated to identify promising candidates for further development.

Encoding In spatially addressable combinatorial synthesis, active compounds can be identified by location. But in other forms of combinatorial chemistry, identifying hits is not so easy because there's often too little of each compound present for characterization with traditional analytical chemistry techniques. Hence, many researchers now use some form of tagging or encoding to label compounds in large combinatorial libraries. The first such encoding scheme was proposed in 1992 by Scripps President Richard A. Lerner and molecular biologist Sydney Brenner at the institute. They suggested that a combinatorial library could be encoded with oligonucleotides

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Continued from page 50 used in assays but also provides greater compatibility with the very small amounts of combinatorial compounds that are typically synthesized on beads. "Instead of 96-well microtiter dishes, which are the current standard in the pharmaceutical industry, you're going to see 1,000-well trays," Gordon predicts. Qntogen's Moran believes that an increased focus on analytical chemistry is needed in the combinatorial field. "One needs to produce a reasonable amount of material in order to characterize any one compound that might be of interest in a library, either by mass spectroscopy or more preferably by proton NMR," says Moran. "The reason for this is that organic synthesis is not straightforward." Different groups added to a core structure will affect the reactivity of library members to a differential extent, leading to possible failures of key synthetic steps. "So one needs to get a handle on how much of each component is being produced and whether you're actually making all the components in your library," he says. "Unless we have good analytical control over our experiments, it's going to be a challenge knowing what one's made." However, another researcher comments that, although it's important to be able to analyze hits, it's not practical or even desirable to analyze all library compounds. Janda believes another key goal for the future is "to create a global library or universal library, where if you screen the library you'd find a hit for any type of target. It might not be a very potent hit, but you'd find a lead. People are trying to create a small library that would be very diverse that would give you leads to almost anything in the drug area. Some people call this combinatorial chemistry's Holy Grail." However, Still says the universal library may prove to be as permanently elusive as the Holy Grail. In combinatorial chemistry, he says, "medicinal chemists . . . design the first library of 1,000 to 100,000 compounds that has a good chance of acting on the target they are going after. Then they screen and make a new sublibrary based on the structure-activity relationships they find. I don't think any medicinal chemist would believe any single library of 10,000 compounds, no matter how carefully chosen, will contain leads for every medical target." 54


Still displays gas chromatogram used to decode a single bead encoded with chromatographically resolvable organic tags. Schreiber suggests that combinatorial molecular recognition could become a fundamental tool for understanding protein function. One of the ultimate goals of the Human Genome Project is to discover the functions of human proteins, he says, and up to now this has been done with molecular biology techniques. "Virtually all studies of the functions of proteins today involve making mutations in the genes that encode proteins and studying the effects," he explains. "This genetic approach to studying protein function is very powerful, but it is very slow and very inefficient. It's going to take centuries to study the function of all the proteins encoded by the human genome this way, and that's simply unacceptable." In principle, this problem could be solved, he says, by using a "chemical genetics approach—where instead of making mutations in the gene encoding the protein you attack the protein itself by using organic ligands that bind to it." And such ligands can best be identified with combinatorial methods. Hence, says Schreiber, "Chemical genetics could be the way in the future to solve the problem of protein function. There's a big advantage if you do it that way—because the very act of understanding protein function gives you a molecule that actually alters function. In terms of medical applications of the knowledge we seek, that's what one is ultimately trying to do." Combinatorial chemistry, coupled to structural biology and cell biology, "is

the most likely avenue to solve the protein binding problem," he says. "If we can combine those techniques, the consequences will be very exciting. It will lead to an era where biology is intimately coupled to chemistry, and where one might even say that chemistry, rather than genetics, will drive biology." The ultimate usefulness of combinatorial chemistry for drug discovery and other applications remains to be proved. But Lilly's Kaldor—whose group developed by combinatorial means the CNS agent that has advanced to the clinic—is one researcher who is cautiously optimistic. "These techniques are more broadly applicable than crystal-structure-guided design methods because you don't have to have any knowledge of your receptor in order to apply them. ... You can develop a pharmacophore hypothesis much more quickly than you might have otherwise been able to do so. To date, we have used combinatorial chemistry for lead generation or lead optimization in over 50% of current Lilly projects and anticipate this percentage will increase with time." Lilly's development of the CNS compound took less than two years from target identification to the beginning of clinical trials. This is "very fast," says Kaldor, "and we, of course, are being challenged by our management to repeat this success in every project we work on. . . . It's a stunning example of what can be done if . . . you apply combinatorial chemistry." D

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Combinatorial chemistry becoming core technology at drug discovery companies Ann M. Thayer C&EN Northeast News Bureau odern drug discovery efforts are exploiting at least three core technologies aimed at increasing the efficiency of finding drug leads: genomics, high-throughput screening, and combinatorial chemistry. Research aimed at deciphering the human genome is rapidly multiplying the number of known disease targets. Saeening methods using biological assays can quickly show if a compound is a "hit"; that is, if it has activity against a target. And combinatorial chemistry methods can produce and help optimize the compounds used in screening. Many pharmaceutical companies view this hot area as technology they must have to compete. In the past, most drugs were discovered by screening collections of compounds to find a random hit. Companies with larger collections or libraries have had an empirical advantage. Although more compounds still can be better, especially with the arrival of high-throughput robotic screening, an expanding knowledge of the molecular biology of disease is shaping the design of these libraries. But speed—which translates into time, money, and an ability to compete—is a key concern in drug discovery. Laborious synthesis methods in which a chemist makes one compound at a time cannot keep up with the desired pace. Combinatorial chemistry—broadly defined by many companies as the generation of numerous organic compounds through rapid simultaneous, parallel, or automated synthesis—is changing how chemists create chemical libraries and is expected to change the speed at which drugs are found. "In the past, the chemist very rightly took pride in having a compound that was very pure because it was expected to have to be active in vitro and to have to go into in vivo models/ explains John L. LaMattina, vice president for U.S. discovery operations at Pfizer's Groton, Conn.-based central research organization. "In running [the new highthroughputl screens, you don't care if there are impurities. As long as you gen-

M

erate some activity, you can figure out a lead structure/' Screening assays also require only small quantities of material. The bottleneck in drug discovery no longer is biology, but rather the number of compounds available, believes LaMattina. Even the large pharmaceutical company libraries, traditionally numbering in the hundreds of thousands of compounds, have become insufficient for screening. New sources of novel compounds are needed. With these realizations, chemists have surmised that small-molecule synthesis can take advantage of automation and robotics, as long as they can have good faith that the mixture being tested consists predominantly of the structure they aimed to synthesize, says LaMattina. "This was the logic that got us to say relatively quickly, 'Let's do chemistry nontraditionally,' " he notes. So, instead of making one compound per week, 100 can be produced in a day. Pfizer is using in-house combinatorial chemistry to enrich its chemical libraries and as an element of its exploratory medicinals group. The company has gone

to outside sources once, setting up a $5 million collaboration with the U.K.based chiral chemistry company Oxford Asymmetry in March 1995. In turn, Oxford Asymmetry created a wholly owned subsidiary, Oxford Diversity, dedicated to combinatorial chemistry. In October 1995, Sepracor, another chiral and pharmaceutical chemistry company, created a combinatorial chemistry subsidiary, Versicor. The Marlborough, Mass.-based Versicor is leveraging Sepracor's existing infrastructure for drug discovery and development and its proprietary chiral chemistries. The subsidiary has been working to develop novel, druglike heterocyclic compound libraries. Other pharmaceutical companies also have stepped up the pace at which they are accessing combinatorial chemistry technologies. Most major drug producers have set up alliances with a new generation of combinatorial chemistry-based drug discovery companies. The interest from pharmaceutical firms, as demonstrated by the more than $500 million pledged to date in R&D alliances, clearly is directed toward small-molecule synthesis. At least another $750 million has been invested in genomic companies to find disease targets (C&EN, Dec. 4,1995, page 18).

Drugmakers partner with combinatorial chemistry firms Pharmaceutical company3

Drug discovery firm

Relationship13

Abbott Laboratories American Cyanamid American Home Products/lmmunex Bayer

ArQule Houghten Pharmaceuticals Houghten Pharmaceuticals

$35 million R&D alliance R&D alliance R&D alliance

Arris Pharmaceutical Pharmacopeia Pharmacopeia Isis Pharmaceuticals Molecumetics Chiron Sphinx Pharmaceuticals Affymax Ariad Pharmaceuticals Selectide Oxford Diversity ArQule Arris Pharmaceutical Houghten Pharmaceuticals Pharmacopeia Pharmacopeia Neurogen ArQule

$70 million R&D alliance $20 million R&D alliance $20 million R&D alliance $100 million R&D alliance R&D alliance R&D alliance $80 million acquisition $533 million acquisition $40 million R&D alliance $58 million acquisition $5 million R&D alliance $30 million R&D alliance R&D alliance R&D alliance $100 million R&D alliance $75 million R&D alliance R&D alliance $50 million R&D alliance

Berlex Laboratories Boehringer Ingelheim Bristol-Myers Squibb Ciba-Geigy Eli Lilly Glaxo Hoechst Marion Roussel Marion Merrell Dow Pfizer Pharmacia Biotech Procter & Gamble Sandoz Pharma Schering-Plough Solvay

a As existed when partnerships were made, b Typical R&D alliance includes equity investment, R&D funding, milestone payments, and licensing fees. Royalties and product income usually are not assumed in total value.


57

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First-generation combinatorial techknown low molecular weight drug that nologies focused largely on peptides and fundamentally has good structural and oligonucleotides. Small companies— desired pharmacological properties and including Affymax, Gilead Sciences, create new analogs through combinatoHoughten Pharmaceuticals, Isis Pharmarial chemistry. Although making anaceuticals, NeXstar, Protein Engineering, logs of known structures runs the risk of Selectide, and Sphinx Pharmaceuticals— creating me too drugs, the same idea can opened their doors in the 1980s when be used in optimizing the activities of automated DNA and amino acid synnovel drug leads. thesizers and sequencers were becoming "Getting the leads is what is most established technologies to produce and important and is what really becomes identify compounds. patentable," explains LaMattina. "We're By late 1994, Eli Lilly had acquired not going to patent a broad library, per Sphinx for $80 million. Marion Merrell se, because its utility would be very Dow then spent $58 million to buy vague." In the past, a drug company did Selectide in early 1995. In March 1995, its best to optimize its lead and then Glaxo paid the premium price of $533 protect its intellectual property by indimillion to take over Affymax, one of the LaMattina: doing chemistry nontraditionally vidually synthesizing as many diverse first, and most technologically sophistianalogs as possible within time and cated, combinatorial chemistry compa- veloping nonpeptide, nonoligonucle- cost constraints. nies. Meanwhile, many pharmaceutical otide small-molecule syntheses. The However, after finding a lead from producers started putting together in- company's basic approach is to use a screening a large combinatorial library, house efforts. series of novel chemical "scaffolds" one can "in theory apply this chemistry Most of the major pharmaceutical that can be combined and attached to patent protection [by creating] thoucompanies have been developing combi- with multiple functional groups to cre- sands of compounds around an active structure and making it very difficult natorial or automated synthesis methods ate diverse compound libraries. during the 1990s, LaMattina believes. He Isis specifically avoids working with for competition to break through," Lacomments that "part of the reason it structures of existing pharmacophores. Mattina says. maybe hasn't been well advertised is "The most value will come from novel To increase the chances of finding that many companies look at these as chemical structures applied to unex- leads, some combinatorial chemistry trade seaets and not something that is plored biological targets," stresses Eck- companies have taken the approach of really patentable/' er. "They then won't be 'me too' com- producing very large libraries. Often, Still, a second generation of combi- pounds [because they will be] structur- combinatorial chemistry gives small natorial chemistry companies has ally different from the things that exist companies chemical libraries that are on emerged with proprietary technologies today and because they are being lev- the same order as those once the domain focused largely on small-molecule eraged at new targets where we don't of only the largest drug firms. chemistries. "It's technology that is have a lot of drugs already." With these libraries and their proprimuch more widely accepted, at least by Analogs of benzodiazepines, the fami- etary technologies, small companies the major pharmaceutical companies, ly of heterocyclic compounds that in- can leverage lucrative deals that inthan most new technologies/' says cludes the major tranquilizer drug Vali- clude large up-front and milestone David J. Ecker, vice president of Isis um, are frequent targets of combinatori- payments, and longer term royalties. Pharmaceuticals, Carlsbad, Calif. "The al programs. The logic is simple: Take a The deals, in turn, give the small comreason is that it's not that much panies access to biological targets different from mainstream drug F " " 1 and the pharmaceutical infrastrucdiscovery in the pharmaceutical ture necessary to take drug candiCombinatorial chemistry adds industry for 100 years. dates through development, clinivalue to drug discovery process "It's just a technical advance that cal testing, regulatory approval, allows you to do things much more and marketing. • Ability to make novel structures/compound classes quickly, but it's not breaking away To generate revenues, ArQule, that much from a tried-and-true Medford, Mass., has drug discov• Ability to control physical/chemical properties in searching chemical space approach," adds Ecker, who also is ery partnerships with Solvay of • Generation of large random or directed managing director of Isis's combiBelgium, Illinois-based Abbott Lablibraries natorial program. "In that regard, it oratories, and Pharmacia Biotech of • Economy and efficiency in synthesis, seems to require much less justifiSweden. After screening ArQule's screening, structure-activity determination cation than something like gene libraries, collaborative efforts with • Compatibility with pharmaceutical screening therapy, something that's new and Abbott and Solvay will work with methods never existed before and people more directed arrays of compounds • Rapid identification of potent leads don't know what all the hurdles to refine the development of specif• Rapid optimization of desired structure are going to be." ic product candidates. • Facilitating synthesis of related structures to While continuing with its antiArQule uses what its calls "modhelp create intellectual property stake sense oligonucleotide programs, ular building-block" chemistries— Isis has devoted a few years to de- I I or groups of reactive monomers— 58


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combined with an automated system for synthesis. According to the company, its solid- and solution-phase chemistries are "robust andflexible"and easily scaled up. One of the company's most recent advances was to produce a small-molecule, peptide mimetic in collaboration with researchers at Brandeis University, Waltham, Mass. (C&EN, July 10, 1995, page 6). Pharmacopeia also leverages its technology through partnering strategies. The Princeton, N.J.-based firm will license its compound libraries to others or will take a partner's selected disease target and conduct biological screening in its own labs to optimize and deliver a drug lead. In the long term, the company plans to identify its own targets and find drug leads. "The tradeoff is always a matter of risk and reward," says Joseph A. Mollica, chairman and chief executive officer of Pharmacopeia. "The path is not completely linear in terms of investment relative to return." Mollica foresees the company focusing only on the early stage of discovery and development. "We'll demonstrate the hypothesis [of a drug lead] in a relevant animal model and then outlicense the compound because there is a lot of investment required before you get to the next big return." Pharmacopeia has already set up some of the largest deals to date. Under an agreement with Sandoz Pharma, potentially worth $100 million, Pharmacopeia is providing the Swiss drug producer with hundreds of thousands of compounds to screen in several drug areas. Sandoz, in partnership with the San Diego-based venture-capital firm Avalon Ventures, funded the start-up of Pharmacopeia and of Argonaut Technologies, a San Carlos, Calif .-based developer of automated organic synthesis instrumentation and reagents. In other deals, Pharmacopeia will receive up to $20 million each from Bayer and from Berlex Laboratories for combinatorial compounds and highthroughput screening against partnersupplied targets. And in a $75 million deal with Schering-Plough, the company supplies compounds as well as conducts screens against cancer and asthma targets in its own labs. In all three deals, Pharmacopeia is to receive royalties on resulting products. Tagging or "split and pool" technologies used by Pharmacopeia and others are considered by some to be "pure" 60


control over the chemistry and in identifying compounds, say many executives, is as or more important than making millions of compounds. For example, Versicor is "developing chemistries that address biological themes," according to company president Jeremy Goldberg. These themes include compounds that mimic protein structures. "There is plenty of room in small-molecule combinatorial chemistry to address shape space using chiral and stereoselective methods ... in a way that mimics the chirality of targeted enzymes or receptors," he says. Mimicking the shape of molecular recognition interactions, many in the field Mollica: technology's power is obvious believe, will enhance the chance of finding drug leads. Molecumetics, Bellevue, combinatorial chemistry, in contrast to Wash., creates small libraries based on parallel synthesis, which keeps synthe- conformationally constrained peptides sized compounds separate. Pharmaco- that mimic protein secondary structures peia's sophisticated tagging methods are such as (3-turns, oc-helices, and (3-sheets. based on work by W. Clark Still of These template libraries are then used to Columbia University and Michael H. synthesize nonpeptide, small-molecule Wigler of Cold Spring Harbor Laborato- drug leads. ry in Cold Spring Harbor, N.Y. Encod"The real proof is in the actual moleing tags allow for the identification of di- cules that you can find, and so we're verse compounds produced in very concentrating to a large degree on comlarge mixtures. ing up with lead compounds and using Mollica argues that Pharmacopeia's those as a source for partnering," says approach allows for the production of Edward Field, director of business designificantly larger, more diverse librar- velopment at Molecumetics. The comies. Parallel synthesis methods are limit- pany currently is collaborating with ed, he believes, by the number of com- Bristol-Myers Squibb. pounds that can be handled or deciSan Diego-based CombiChem, whose phered through analytical methods. technology is also based on work by rePharmacopeia's chemistry focuses on searchers at Scripps Research Institute, heterocyclic structures, he adds, which directs its programs toward gene famiare "the mainstay of the drug industry." lies, says the company's chief operating Houghten Pharmaceuticals, one of the officer, Peter L. Myers. Genomics will first combinatorial chemistry companies, lead to the discovery of multiple recepfounded by Richard A. Houghten of tors and repeated opportunities to sell liScripps Research Institute, has shifted its braries directed at different gene famifocus to heterocyclic, small-molecule lies. Myers and many others in the field chemistry in the past two years. One of believe that combinatorial chemistry will its early peptide-based combinatorial continue to move toward producing drug leads is now in Phase II clinical tri- smaller, more directed libraries. als. Because of the interest in combinatoMyers says CombiChem also is derial chemistry, the San Diego-based com- veloping a "universal signature lipany has set up nine partnerships, says brary" based on the premise that about Robert S. Whitehead, Houghten presi- 10,000 or fewer molecules can repredent and CEO. "Longer term, we'd like sent 'chemical space'—that is, they are to focus internally on a selected series of rich enough in different chemical and our own discovery programs." structural features and geometry to be Many other companies see an advan- capable of interacting with a whole tage in developing smaller, more fo- range of targets. In screening this gencused libraries, and making larger quan- eral library, believers say there is a reatities of each compound. Parallel or ro- sonable chance of finding a hit, even a botic synthesis therefore is amenable poor one, to use as an initial lead. because smaller libraries do not need to "It's a quite different approach from be encoded to be sorted out. Analytical what I call the brute force approach,"

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chemistry software development firm. He notes, for example, that when combinatorial chemistry first started becoming popular a number of people talked about the value of the technoloJames H. Krieger, C&EN Washington The same kinds of questions continue gy in the context of making millions, or to be asked, says Christopher Herd, vice even billions of compounds. What's ' hen combinatorial chemistry president of life sciences at Molecular happened in the past year, he says, is burst upon the drug discov- Simulations, San Diego, a molecular that people are coming around to the ery scene, it had a profound modeling and computational chemistry thought that what's important is not effect on chemical information man- software developer. "You're still dealing the sheer number of compounds but agement. Early on, information man- with targets. You're still trying to deal their efficiency. agement professionals saw that the with recognition of what's responsible Information management systems software systems of the day were not for binding or not responsible for bind- had evolved under the older chemistry up to dealing with the information ing," Herd adds. "But now you're trying paradigm when computer technology management needs of what amounted to answer the questions in a different began to be directed toward chemical to a paradigm shift in the performance way and more qualitatively." applications in that precombinatorial of chemistry. Yosef Taitz, chief executive officer of chemistry world. One of the information Combinatorial chemistry, after all, Daylight Chemical Information Sys- management challenges was to provide turned traditional chemistry upside tems, Irvine, Calif., another information a way for companies to keep track of their chemical creations. down. It required chemists to think not in terms of syntheAs chemical companies— sizing single, well-characterpharmaceutical firms in parized compounds, but in terms ticular—synthesized molecule of simultaneously synthesizafter molecule in a search for ing large populations of comdrug screening candidates, pounds. It also required that they needed to have records of those people involved with inwhat their chemists had synformation management and thesized, how they had done computational chemistry sysit, how the compounds had tems address the same issues fared in screening, and so as the chemists. The informaforth. Hence, early versions of tion systems, too, had until information management systhen dealt essentially with one tems were aimed at creating molecule at a time. corporate databases of individual compounds in formats "Technology such as combithat enabled researchers to natorial chemistry and highsearch the databases in a varithroughput screening generate ety of ways, including, for exmasses of relatively unrefined Molecular models of compounds from a library—in this case data—data that are certainly more than 1,200 analogs constructed combinatorially by ample, substructures. less refined than what chem- alterations at three different sites in a single But the advent of combinaists produced in the past/ 7 angiotensin-converting enzyme (ACE) inhibitor—can be torial synthesis and the robotsays Steven Goldby, president arrayed on a computer screen in various patterns. ics employed brought an overand chief executive officer of whelming increase in the volMDL Information Systems, San Lean- management software firm, character- ume of structural, biological, and other dro, Calif., an information manage- izes the effect of all this on information data that needed to be stored and ment software firm. It's become more management software as "an explosion available for searching. Not only volimportant than ever for companies to of demands." ume changed. So, too, did the uses to be able to handle this flood of data, he When it first began, combinatorial which researchers doing combinatorial points out. "Information management chemistry focused on synthesis of large chemistry put the information and ofis absolutely critical in today's research molecules, essentially peptides and oli- ten the form in which they needed it. environment." Information management is a critical gonucleotides. More recently, the emAlan Engelberg, product manager phasis has swung to nonpeptide small element of essentially all steps involved for MDL's combinatorial chemistry line molecules—those with molecular in a combinatorial synthesis project. of products, puts it similarly. Instead of weights under 500 daltons. Typically, a project begins with planning making a specific compound and then At the same time, some observers for a chemical library. The library is a doing a limited amount of screening, have noted a shift in emphasis from population of molecules to be produced he says, chemists are creating a huge sheer quantity to greater selectivity. as discrete compounds or as mixtures of amount of information. "So you have One of those observers noticing this compounds that can be biologically an individual chemist actually being shift is Mark W. Schwartz, vice presi- screened for activity against a desired much more productive, but in a less re- dent of marketing at Tripos Inc., St. target. From the planning stage, the fined way." Louis, a modeling and computational project continues through building of

Combinatorial chemistry spawns new software systems to managefloodof information

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FEBRUARY 12,1996 C&EN 67

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tions, it uses hyphens, equal signs, and number signs for single, double, and triple bonds. For example, carbon diox• Build, edit, and rotate 3D molecular models. ide is represented as 0=C=0 and acetic • Organics, inorganics, crystals, polymers, etc. • Export beautiful graphics to your word proacid as CC(=0)0. Computer programs cessor, spreadsheet, drawing program, etc. reading SMILES use it as a character • Draw 2D Lewis diagrams and convert to 3D. string, a molecular graph, a database • Spacefill, Ball-n-Stick, and Wire Frame styles. index, source code for a substructure • Supports current Windows/MacOS printers. search, and so on. Chuckles expresses chemical structure at the "monomer" or molecular chunk level, rather than at the atomic level. Monomers are defined for each application and stored as a monomer Includes: expandable 3D Structure Library, graphical point-n-click 3D Builder, 3D Syntax table in a file. For example, glycine— Checker, interactive Visual 3D Editor, 3D NCC(=0) in SMILES—would be Gly in Cleanup structure optimizer (energy minimi Chuckles; likewise, hydroxy—[OH] in zation), Coach Lewis tutorial on 2D Lewis dia SMILES—would be Oh in Chuckles. grams, complete manuals, more. Easy-to-use! Chortles extends Chuckles to represent CIRCLE 5 8 ON READER SERVICE CARD regular mixtures, where multiple monomer choices in a given position are indicated by semicolon-separated Clip Art for Chemistry monomers in brackets. Daylight says that with its linguistic Ver 3.0, Windows, MaeintoshtySWl approach, the monomer concept, and Superb collections of professionallyTflFavfn, fu% color, finely-detailed (vector) line art. Scale and Chuckles and Chortles as languages, it rotate with no "jaggies." Glassware illustrations has pretty much got all the requireare modular (same style & perspective). Combine them to create new images. Includes ments covered for what might be comfully illustrated manual. Over 1,000 images! ing up in combinatorial chemistry. Vol 1: Basic Glassware & Setups (100 images) Vol 2: Advanc'd Glassware & Setups (250 images) "There might be some challenges," Vol 3: Micro Glassware & Setups (175 images) says Taitz, "but definitely not major Vol 4: Benchtop Devices & Instrum't(100 images) Vol 5: Safety, Lab Wear & Symbols (265 images) challenges that we cannot overcome or Vol 6: Education, Concepts, 3D Basics(140 images) modify." Vol 7: Industry, ChemEngr'g, HazMat( 50 images) Macintosh includes both EPSF and PICT formats. A new major release of the Daylight Windows includes both EPS and WMF formats. product slate, release 4.5, is imminent. A feature of the release applicable to combinatorial chemistry is that SMILES is being further extended to handle reactions. Among the release's capabiliIf ^ ^ • ^ Urn • 4 ties are a reaction toolkit, with support for reactions, reaction patterns, reaction searching, and transformations. And THOR and Merlin servers will be upgraded with reaction-handling capabilities for database building, retrieval, and searching. Daylight will have a ^^^^^^mm^^^^^^^^y^,] —•• :i beta version of 4.5 by the end of this month and expects to formally release it sometime between April and July. |Any vol: $3925. Any 3LvpS: $69SS."Glassware11 MDL's approach to combinatorial pl|pll|llillllp^^ chemistry is embodied in its Project LiWJ " "qgagsff^^ brary software, introduced about a year CIRCLE 5 9 ON READER SERVICE CARD | ago. Project Library is a desktop softFor Info & Sales: I ware application, designed, as its name suggests, for use at the project level to manage the chemical and biological data coming from combinatorial syntheses. It Molecular Arts Corporation teams with MDL's ISIS (integrated scien(714) 634-8100 · FAX (714) 634-1999 tific information system) to manage ininternet: [email protected] formation flow throughout the combinatorial chemistry process. For example, Project Library enables

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a researcher to build, store, search, and archive combinatorial chemistry and associated biological data. The combinatorial libraries can include specific structures represented as discrete compounds. Or they can incorporate generic structures that represent hundreds to millions of specific compounds, along with building blocks or fragments of molecules that represent R-groups attached to the basic generic structures. An extension of the MDL approach is now on the drawing boards. A new software product called Central Library is a critical element in MDL's long-term combinatorial strategy, according to Goldby. "It will be the principal focus of our combinatorial efforts for the next year or two," he says. Whereas Project Library deals with restricted sets of data that scientists are generating in their own project, Central Library will enable scientists to integrate combinatorial data with existing corporate compound data and bioassay data at any step in the workflow process. "Eventually," Goldby says, "Project Library will act as the client to Central Library. And so we will have a client/ server solution in this marketplace." In recent years, MDL has established a particularly close relationship with molecular modeling and computational chemistry software developer Biosym Technologies and with computer manufacturer Silicon Graphics. The idea was that each of the companies would pay particular attention to making sure its products meshed smoothly with those of the other partners. That relationship has continued following last summer's merger of Biosym and Molecular Simulations. The merged company has just announced that in late March it will be known as Molecular Simulations Inc. (MSI), with headquarters in San Diego. It also has announced a combinatorial chemistry software product of its own, called C2 • Diversity. Marvin Waldman, director of rational drug design at the company, explains that C2- Diversity was basically developed to provide a guideline for design and analysis of combinatorial libraries. It is designed to maximize the coverage of property space, enabling the selection of the most diverse R-group fragments or whole molecules that give the broadest span of various 2-D and 3-D descriptors that have been found useful in QSAR.

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Advaneed 3D C2 • Diversity is a module that plugs into the company's Cerius2 molecular modeling environment and product line, designed so that users can tailor the system to their particular research needs. Hence, the Cerius2 software developer's kit (C2 • SDK) can be used by customers to incorporate their own customized functionality into C2 • Diversity. Because of the high demand for combinatorial chemistry software, Waldman says, MSI decided to make C2-Diversity available now as what it calls an early access product. The official commercial release is planned for June. Waldman explains that the current product is reasonably robust and, although the level of documentation isn't what it will be in June, the software basically contains all the functionality. As a long-term strategy to help guide its development efforts, Biosym had formed a number of consortia that brought together representatives from the consortium members with the software company's scientists and programmers to focus on specific areas of technology. That approach has continued in the merged company, and MSI now has a newly formed Combinatorial Chemistry Consortium. According to Judith Hempel, director of collaborative R&D for life sciences at MSI, the consortium will address the issues of protocols and procedures for assessing diversity and sampling and designing libraries. One specific goal, she says, is to develop software with next-generation methods for 3-D selection and comparison of molecules. Chemical Design, a molecular modeling and computational chemistry software development firm headquartered in the U.K., with U.S. operations in Mahwah, N.J., last year formed its own Combinatorial Chemistry Special Interest Group. The group was estab-

lished, according to the company, to make sure that Chemical Design's ChemDiverse software meets today's requirements. ChemDiverse is a module for the company's Chem-X molecular modeling and computational chemistry software. A feature of the system is its use of pharmacophore plots to give a picture of the pharmacophores found for a combinatorial library and therefore the diversity of the library or mixture. Pharmacophores are those structural features of a molecule required for particular biological activity. For the 3-D plots, axes represent distances between interaction centers, with each symbol depicting a particular pharmacophore type and geometry. The plots can thus be used to visually compare the diversity of different libraries. The challenges faced by the software development firms aren't trivial, as evidenced, for example, in the observations of Columbia University chemistry professor W. Clark Still. Some of what is being done with computer software for combinatorial chemistry— database software to register compounds in libraries, for example—is needed and going to be useful, Still points out. On the other hand, he says it is not clear that other types of software—those that claim to measure diversity or to allow intelligent compound picking, for example—give valid and reliable answers. "The problem," Still explains, "is that it is easy to develop a reasonable algorithm and to program it, but it is much more difficult to establish the validity or utility of the algorithm in a scientifically convincing way." Whatever their individual approaches, though, the software development firms are pouring a great deal of effort into an attempt to make that happen as the field of combinatorial chemistry develops. •

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For Info & Sales: Molecular Arts Corporation (714) 634-8100 • FAX (714) 634-1999 Internet: [email protected]

• • H O K

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FEBRUARY 12,1996 C&EN 73

COMBINATORIAL CHEMISTRY - C&EN Global Enterprise (ACS

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