COVER STORY KEEPING FAITH Bayer AG is one of the few major pharmaceutical companies that still maintains a significant natural products drug discovery effort.
BETTING ONI NATURAL NATURAL : 0R CURES PRODUCTS FOR In natural products drugg discovery, traditional, as well as novel, approaches :hes are being applied A. MAUREEN ROUHI, C&EN WASHING3T0N
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ATURAL PRODUCTS ARE STILL
delivering candidates to development pipelines over a wide range of therapeutic areas. For this reason, some big and small companies continue to bet on natural products as a source of cures and life-improving drugs. Not all of the big pharmaceutical companies jettisoned their natural products programs in the 1990s. And among many smaller companies, natural products are the primary, if not the sole, source of leads for drug candidates. Bayer, Merck, and\vyeth are major drug companies that have remained committed to natural products drug discovery "Natural products have been and will be important sources of new pharmaceutical compounds," says Matthias Gehling, Bayer's head of natural products research. His group provides natural products for screening over all therapeutic areas of interest to Bayer. To make natural products competitive, the group has reduced processing time of crude extracts through pretreatment, automated separation, and computer-assisted structural elucidation. "By HTTP://WWW.CEN-ONLINE.ORG
optimizing the technology platform around natural products research, we have made great gains in productivity," he tells C&EN. Merck also has an active natural products effort, but it no longer has a formal natural products drug discovery department, as it did until 2001. According to Malcolm MacCoss, head of the basic chemistry group, the efforts are focused on spécifie therapeutic areas, such as infectious diseases, where the likelihood of success is highest. In fact, last year Merck launched the new antifungal agent caspofungin acetate (Cancidas), a derivative of a natural product from the fungus Glarea lozoyensis. Although Merck invested in combinatorial chemistry early on, MacCoss says, Merck did not embrace it to the same extent that other companies have. "We have kept all our avenues open," he says. "Both combinatorial chemistry and natural products are tools in our toolbox."
At'vvyeth, the natural products program is "solid," says Frank E. Koehn, associate director for natural products and structural chemistry The company still adds to its natural products collection and maintains libraries of cultures (mainly microbes, but also some marine organisms and terrestrial plants), extracts, extract fractions, and pure compounds. Three natural-productbased candidates are in the pipeline. CCI779, a rapamycin ester, is in Phase III clinical development for treatment of renal cell carcinoma and in Phase II for treatment of breast cancer. MAC-321, a novel taxane, and HTI-286, a synthetic analog of the natural product hemiasterlin, are being studied for treatment of various cancers. But, Koehn emphasizes, "we don't do natural products here at Wyeth the way we did 15 years ago." Natural products the old-fashioned way can't keep up with the shorter and shorter timelines of modern drug discovery, he explains. " Y)u must use all the tools at your disposal to make natural products have an impact—technology, the research approach, and just the way to think about natural products. "For example, structure determination used to be the major bottleneck, but not anymore," Koehn says. "You need to configure your research to take advantage of that. Now, detecting activity, characterizing the compound, and getting enough pure material to assess value are the most important components. Ύο\χ need to know quickly whether your hit is viable. Y>u need good analytical tools and databases." ON THE OTHER HAND, some major drug companies have drastically reduced their natural products efforts or even eliminated them. Last February, for example, Eli Lilly transferred its natural products collection with its related libraries and databases to Albany Molecular Research, Albany, N Y . Howev er, Eli Lilly continues to screen some of its targets against natu ral products through a collabo ration with Albany Molecular, according to BarryA. Berkowitz, a corporate vice president at Al bany Molecular. Observers saythis type of outsourcing may now be the most efficient way for big pharma to handle natural prod ucts drug discovery C&EN
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The diversity of natural products is integrated with other sources of chemical diversity and other technologies such as informatics and computer-assisted drug design in Albany Molecular's drug discovery efforts, Berkowitz says. With more than 200,000 sources and 160,000 purified and preseparated samples in wells, the collection, he adds, "is one of the largest sources of chemical diversity for drug screening in the world." Licensing is another way to develop drugs based on natural products. Advanced Life Sciences, a drug company based in Woodridge, 111., acquired its most advanced drug candidate through this route. Calanolide A, a natural product from the island of Borneo, is now in Phase II clinical trials for the treatment of HIV. It was first identified by the National Cancer Institute (NCI) through its H I V-screening program. Michael T. Flavin, the chief executive officer ofAdvanced Life Sciences, says the compound caught the company's attention when it learned that N C I had only a few milligrams of the compound and could not find more from the plant source. "Being chemists, we said, 'Let's make the material,' and we did," Flavin tells C&EN. "We worked out a method under a Small Business Innovation Research grant. And then we asked N C I for an exclusive worldwide license to develop the compound into a drug." Manufacture of the drug for clinical studies has been contracted to chemical companies in the U.S. and Western Europe, he adds. Another candidate that Advanced Life Sciences has in the pipeline is betulinic acid. This potent compound against malignant melanoma was isolated by the University of Illinois, Chicago, and identified through NCI's cancer-screening program. It will enter Phase I clinical trials in early 2004, according to Flavin.
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GOVERNMENT ORGANIZATIONS like NCI, as well as academic institutions, can identify promising compounds, but they are not set up for clinical development and clinical trial management, Flavin says. "Building on what they have done, companies like ours can develop specific leads through license agreements," he says. "That's the kind of cooperation that's needed today to develop leads all the way to the market." Neither Albany Molecular nor Advanced Life Sciences focuses exclusively on natural products for drug discovery. At several companies, however,
Caspofungin acetate H A R V E S T Pneumocandin B0 (crystals shown at top), a natural product produced by Glarea lozoyensis (middle), is the precursor of Merck's new antifungal drug.
drug discovery is primarily based on natural products. For example, PharmaMar, a Spanish drug company specializing in anticancer drugs, examines marine natural products exclusively The company, which has a collection of about 4 0 , 0 0 0 marine organisms, "believes strongly that the sea can be a source of anticancer compounds," says José Luis Alonso, the company's drug discovery manager. So far, the collection has yielded about 150 anticancer compounds, of which 14 are preclinical candidates, five are in late-stage evaluation, and four are in clinical development. One has received marketing authorization: aplidine (Aplidin), a cyclodepsipeptide from the tuHTTP://WWW.CEN-ONLINE.ORG
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COVER STORY mczteAplidium albicans, has been approved in Europe for acute lymphocytic leukemia, Alonso says. PharmaMar's most advanced drug can didate is ecteinascidin-743 (Yondelis), from the sea squirt Ecteinascidia turbinata. Alonso expects that it will be available in Europe for treatment of soft-tissue sar coma by early 2004. Other candidates in development for treatment of solid tu mors are kahalalide F, derived from the sea slugElysia rufescens (Phase II), and ES285, from the Atlantic clam Mactromeris polynyma (Phase I). Ecteinascidin-743 for clinical trials has
Natural products drug discovery at PharmaMar comprises the classic activi ties of collection, screening, chemistry and development. As a small company, Phar maMar occupies a niche where natural products drug discovery is more efficient than in the industry as a whole, Alonso says. ALSO EXPLORING the aquatic environ ment is Mera Pharmaceuticals, based in Kailua-Kona, Hawaii. It is particularly interested in microalgae, specifically cyanobacteria. These organisms produce natural products with unusual structures and rich bioactivities, but they have been impossible to exploit because of the lack of scalable fermentations. Mera believes it has the technology to over come that hurdle. T h e company is only 15 months old and is still trying to assemble financing, says Dan Beharry, its CEO. Its business plan calls for an internal dis covery program concentrating initially on antibacterial and an tifungal compounds. It plans to build a large high-quality library of novel, bioactive compounds. Automated processes will be developed to work up extracts and to frac tionate and characterize compounds. Ef forts will be made to concentrate minor compounds to detectable amounts. That should reveal new structure types that are patentable but have not been accessible before. The library will be backed up by ample amounts of microalgal cultures, so
"It's a shame that many of the big pharma companies got out of natural products just when technology was so dramatically improving the process." been obtained from the natural source grown by aquaculture, Alonso says. A total synthesis in 1996 by Harvard University chemistry professor E.J. Corey's group was not practical for large-scale amounts. PharmaMar scientists later developed a more practical route [Org. Lett., 2,2545 (2000)]. Development of efficient and scalable syn thetic and biological routes for its candi dates is a key element in the company's strategy, Alonso adds.
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that when screening identifies a hit, more material can be produced as needed. Steven J. Gould, who was Mera's chief scientific officer until last month and who previously headed Merck's natural prod ucts drug discovery department, notes that one of the drawbacks of natural products drug discovery has been the lack of back-
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up samples. W h e n he joined Merck in 1997, he says, if an extract was active, usually the organism had to be regrown to produce more material. His experience at Merck taught him, he adds, that when resupply is delayed, for whatever reason, "the experience colors other people's view of natural products for a very long time." The practical problems "are much more manageable by new companies that are starting from scratch and don't have the traditional baggage that has encumbered big pharma," Gould says. In Australia, two start-up companies are betting on natural products. Cerylid, based in Richmond, Victoria, has a collection of plants, marine invertebrates, and microorganisms from Australia, Antarctica, Malaysia, and New Guinea. Entocosm, a spin-off from the Commonwealth Scientific & Industrial Research Organization, has a collection of mostly insects and some terrestrial invertebrates from Australia. Cerylid has three drug leads based on natural products. The most advanced is CBL 316, an anticancer compound isolated from the bark of a Malaysian tree. Initial tests show that it is comparable with or superior to the anticancer drugs doxorubicin, paclitaxel, and etoposide. "The supply is problematic," says R. MurrayTait, Cerylid's vice president for drug discovery "But we have an active program, and we're talking to several companies for synthesis." Tait will reveal neither the structure nor the identity of the source tree. In addition, Cerylid has assembled libraries of pretreated extracts that have been prescreened for specific activities. For example, OncoDDL is a collection of extracts with confirmed activity against one or more of a panel of seven human tumor lines. Another library is BacDDL, for antibacterial activity MycoDDL, for antifungal activity, is still being developed. Cerylid has a program to screen its libraries against targets of other companies, Tait says. Some of its current partners are Aventis, Anadys, and a major Japanese pharmaceutical company Cerylid claims intellectual property rights on compounds in its libraries. If the partner finds a hit, Cerylid determines the active compounds and reports their structures. The partner then has the option to evaluate compounds further and to take a license, Tait explains. "It's a shame that many of the big pharma companies got out of natural products just when technology was so dramatically improving the process," Tait says. "It has been left to small companies like Cerylid and others to push ahead, implement new HTTP://WWW.CEN-ONLINE.ORG
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COVER STORY approaches, streamline the process, and make it more competitive with combina torial chemistry." Entocosm is also only 15 months old and still focused on getting financing. Stephen Trowell, the company's chief scientific and chief operating officer, thinks the compa ny will be operational by the end of 2003. "The chemistries of insects and other terrestrial invertebrates are still practical ly untouched as drug discovery leads," Trowell says. "Some insect chemistry has been done but largely in the name of chem ical ecology People have not really both ered to ask about bioactivities in relation to human diseases. We hope that because we're in there first, we will be able to pick the low-hanging fruit." THE COMPANY'S PLAN is initially to dis cover antibiotics and develop them up to Phase I clinical trials, then to license out or partner. "Antibiotics are relatively amenable for a small company," Trowell explains. "Because the models for bacter ial infections are highly predictive, the at trition rates at later stages of drug devel o p m e n t are n o t as high as for other diseases," he says. Entocosm's collection is yielding new molecules with the complexity of steroid hormones and with molecular weights ranging from 300 to 500, Trowell says. "These would be moderate synthetic chal lenges, not in the league of bryostatin and other complex multiring marine natural products. But they are complex enough to be drugs." Entocosm's first drug candidate might well originate from so-called nasute ter mites. Soldiers of these termites, instead of being armed with powerful mandibles, have a nozzle in the middle of their fore head, Trowell explains. "When the nest is disturbed, the soldiers rush out and squirt sticky stuff through the nozzle. The in vaders get tangled up in the toxic glue."
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The termites produce compounds based on the trinervitane skeleton, Trowell says. The company has completely character ized one compound that is inhibitory at 25 μg per mL, about 10 times less potent than a clinically practical antibiotic. "But
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it's not a bad starting point," he adds. "Oth ers following it are significantly more po tent. We're now looking at synthesis and structural optimization, and we're talking to people who will work with us." Entocosm's libraries will be available to other companies for screening on a caseby-case basis, Trowell says. "One of our ad vantages is exclusive access. The barrier to entry in this field is quite significant right now. We won't provide material on a feefor-service basis. We would be interested only in alliances around certain therapeu tic areas. WëU screen together; we'll do the natural products chemistry; but when it comes to drug development, we'll hand it over to the partner." Trowell says interest in natural products is returning. "Somebody who spent 10 years at the top of one of the world's leading pharma companies said to me, T h e people who moved away from natural HTTP://WWW.CEN-ONLINE.ORG
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COVER STORY COMPREHENSIVE Albany Molecular Research says its repository of natural products samples, which includes Eli Lilly's collection, is one of the largest in the world. products have left our pipeline emp ty,'" he tells C&EN. "The other thing is, I thought it would be very difficult to get this company fund ed. But investors are interested. These people take top advice. They wouldn't put their money on the line for a bad idea." IN OTHER COMPANIES, natural products drug discovery is nontraditional. For example, at Kosan Biosciences, Hayward, Calif, drug dis covery is based on mastery over nature's polyketide-manufacturing apparatus. Many valuable drugs— such as erythromycin, tetracycline, lovastatin (Mevacor), and simvastatin (Zocor)—are polyketides. Kosan's technolo gy allows it to not only put the genetic in structions for polyketide biosynthesis into
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organisms that are easy to grow but also to manipulate those instructions to modify existing polyketides or to create entirely new ones.
"Two historical shortcomings of natural products are the difficulty in chemical derivatization and the small quantities available from na ture," says Michael S. Ostrach, Kosan's president and chief oper ating officer. "Our technology solves both those problems. We can do microbial medicinal chemistry and get microorganisms to overproduce the compounds we want." Ostrach says Kosan was founded on the idea of making new, nonnatural polyketides by mixing and matching DNA codes. But the company has decided to focus on improving products already in the market. The approach is lower risk and much more lucrative, because those products already have been biologically and commercially vali dated, he explains. Kosan's most advanced program is the natural product epothilone D (epoD), which is being developed in col laboration with Roche. The group of Samuel J. Danishefsky, a chemistry pro fessor at Columbia University and director
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INSECT CHEMISTRY Nasute termites...
... are rich in trinervitane compounds
R1'11
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of the Laboratory of Bioorganic Chem istry at Sloan-Kettering Institute for Can cer Research, New York City, first discov ered epoD during its total synthesis of epothilone Β (epoB). Other scientists lat er discovered that epoD is produced in na ture by a microorganism as an intermedi ate in the biosynthesis of epoB. "Danishefsky synthesized epoD, tested it, and decided it was better than epoB," Ostrach continues. "We took his data and combined it with our ability to overpro duce natural products. We took the entire set of genes from the native producer, re moved the enzyme that converts epoD to epoB, and now we have a recombinant or ganism that produces epoD but not epoB." EpoD will be entering Phase II clinical tri als later this year. "We believe it is the first small molecule being tested in humans that is produced recombinantly," he adds. EpoD is an unaltered natural product. Another strategy, microbial medicinal chemistry by genetic engineering, is ex emplified by a collaboration withJohnson & Johnson to produce third-generation macrolide antibiotics. Here, the erythro mycin backbone is altered in a way possi HTTP://WWW.CEN-ONLINE.ORG
ble by genetic engineering but not by syn thetic chemistry Compounds derived this way are in preclinical evaluation, Ostrach says. By enabling changes to existing prod ucts, Kosan's technology makes it possible for the company to jump intofieldsthat are heavily patented with proprietary mole cules, he adds. "Nature has been so great at identifying leads," Ostrach tells C & E N . "We are exploiting those leads to make products based on es tablished mechanisms for es tablished markets. Someday, we will go back to making brandnew polyketides." Kosan's technology is avail able to others—but only if the company can have a healthy share of revenues from com mercialized products, he says. "Much of big pharma moved away from natural products, I think to their regret," Ostrach says. "They thought they could rely on combinatorial chemistry, but that has been singularly unsuccessful. If the hurdles of traditional natural products
drug discovery can be overcome, we will have many more successful drugs from nat ural products. Our technology solves two of the most important barriers—mass pro duction and chemical optimization." MANIPULATING GENES is also the strat egy of Naprogenix, a Kentucky-based start-up company that grew out of re search at the Kentucky Tobac co Research & Development Center (KTRDC), Lexington. The company believes that by probing useful genes in plant genomes, it can make plants express a host of natural prod ucts that have never been seen before. The usual practice of sam pling plants and analyzing them reveals only the chemicals that are being expressed on a partic ular day and time, depending on the stress es —insects, weather, or disease—the plant is responding to, says H. Maelor Davies, director of KTRDC. "We now know that plants have many more natural products
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COVER STORY pathways, but they are expressed only un der certain conditions. The hidden chem ical diversity is apparent at the genome lev el, and we are now poised to reveal it." To uncover that hidden chemical di versity, Naprogenix randomly mutates large populations of plant cells and screens the resulting culturesforcompounds of inter est, saysJohn Littleton, a professor of mo lecular and biomedical pharmacology at the University of Kentucky, Lexington, and chief biomedical research officer of Naprogenix. "We then establish what the compounds are and what bit of genome has been activated to produce them," he adds. Other groups are manipulating plant genomes but largely through use of whole plants. By doing it at the cell culture level, Naprogenix can produce a lot of clones of mutated cells very rapidly, and sourcing an interesting compound would not be quite so burdensome, Littleton says. For now, Naprogenix is testing its ideas on tobacco, but the same general approach can be used with any plant. "As more plant genomic information be comes available, it would be possible to
ANTICANCER BREW At Kosan Biosciences, 1,000-L fermentors are producing epothilone D for clinical trials. establish what particular plants would be good sources of specific com pounds that might be of value to drug discovery," Littleton says. Accessing chemical diversity by ge nomic manipulation is not unique to plants, he adds. "But plants are a particularly good source of chemical diversity, and that's why we are inter ested in them." Meanwhile, at Galileo Pharmaceuticals, Santa Clara, Calif, natural prod ucts are key in the search for drugs to treat inflam matory metabolic, and neo plastic diseases arising from defects in redox signaling.
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"Natural products participate in numer ous reactions involving redox chemistry," CEO Guy Miller says. "If we omit natural products from our programs, we would be overlooking a significant portion of chem ical space where redox-based molecular scaffolds reside." The company is using the similarities in the redox biochemistries of plant and animal systems to explore the therapeu tic utility of plant secondary metabolites that are induced by stress. For example, a stroke, which is a disruption of blood flow in the brain, "leads to immediate al terations in charge-transfer reactions that trigger a host of pathologies, in cluding inflammation," Miller explains. The company models analogous bio chemical events in plant culture systems and examines the secondary metabolites produced in response to the stress. It has isolated several novel redox-based charge-transfer scaffolds, which have served as templates for construction of libraries with charge-transfer attributes. Galileo's approach has attracted 10 pharmaceutical partners and has yield ed several novel chemical scaffolds that are being developed against inflamma tory, metabolic, and neoplastic targets. One compound will enter clinical trials within a year for a rare indication of a neuroinflammatory disease, Miller says. In addition, Galileo has partnered with a major U.S. pharmaceutical company in a double-digit million-dollar deal to bring candidates to clinical trials for dermato logie inflammatory disease within 12 to 18 months. And it is negotiating partner ships to move to the clinic candidates tar geting other inflammatory indications such as cardiovascular disease and macu lar degeneration. The charge-transfer chemistry that un derlies biology is "highly underexploited for drug discovery" Miller says. Now, redox system malfunctions are known to be in volved in diseases. "Our pioneering work in rational design of charge-transfer mo lecular scaffolds, keying off of nature's adaptive responses to redox malfunctions, is the differentiating element of our drug discovery program," he adds. Natural products have fallen out of fa vor in certain sectors of the pharmaceuti cal industry But some drugmakers con tinue to be confident that nature's wellspring will keep on yielding valuable human cures. "The point is not that natu ral products will solve all problems," Gould points out. "It is that a lot of problems are not being solved because natural products are not being examined." • HTTP://WWW.CEN-0NLINE.ORG
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