Natural products research at the NIH
National Cancer Institute-Frederick Cancer Research and Development Center
February 2010
Pharma Matters interviewed David J. Newman, Chief of the NCI Natural Products Branch of the Developmental Therapeutics Program, to gain an insight into the chemistry behind his research into natural products.
Newman trained originally as an industrial analytical chemist, then received his M.Sc. (1963) in synthetic Organic Chemistry (University of Liverpool, U.K.). After some years in the U.K. chemical industry he received his D.Phil. (1968) in Microbial Chemistry (University of Sussex, U.K.). Following postdoctoral studies (Biochemistry Department at the University of Georgia), he joined SK&F Laboratories in Philadelphia, PA, and spent 15 years in biological and antibiotic discovery chemistry. After six years in various biotechnology and pharmaceutical companies working mainly in marine natural products, he joined the Natural Products Branch (NPB) in 1991 as a chemist responsible for the marine and microbial collection programs and was appointed Chief in 2006. Has published over 100 research papers, reviews and book chapters, and holds 18 patents.
Q. What is your approach to natural products (NPs)?
The remit of the NPB is to find novel leads to agents that may be of utility as anti-tumour drugs. Note, not drugs per se at this stage, but structures be they old or new that have the biological potential to lead to drug candidates. To do this, we have, over the years, run collections for plants, microbes and marine organisms. We currently have over 140,000 plant, 30,000 marine and roughly 30,000 microbial extracts.
Q. What day-to-day chemistry do you do?
Both basic and at times rather esoteric bioactivity-driven isolation processes that rely extensively on HPLC-MS and UHPLC-MALDI-TOF instrumentation, coupled to extensive databases, both in-house and commercial. Access to standard spectroscopic instruments is part of the process, though we also have extensive instrumentation attached to the HPLC-MS trains in addition to the mass spec.
Q. How does this research mesh with NCI aims?
The Developmental Therapeutics Program which NPB is part of, has the express aims of discovering and
developing up through preclinical trials, agents from both natural and synthetic sources that have the potential to enter clinical trials as potential antitumour agents. There is another Program, known by the acronym CTE P (Clinical Trials Evaluation Program), part of whose job is to take molecules that we produce and conduct clinical trials on them. We accept molecules from any source and carry them through the system at Uncle Sam’s expense, even up through Phase II clinical trials. For the molecules that come in at the early DTP level, they all go through the 60 human cell line panel and if justified into early in vivo assays with no IP being taken by NCI. NPs definitely mesh with NCI’s aims.
Q. How do you assess NPs?
Part of the initial process at the crude extract stage is an assessment of their “cytotoxicity” in the 60 cell line screen at 1 dose level. Those above a certain nominal level then proceed to the regular 5 dose 60 cell line screen. A decision is then made as to dropping it or continuing.
Q. What challenges do you face in general?
Access to countries in order to collect materials for investigation. What has occurred is what my old Chief (Gordon Cragg) and I have called the "Myth of Green Gold", where totally unrealistic expectations have been foisted upon developing countries, often by developed country organizations, such that the idea that a patent means a drug with millions of dollars of income has become paramount. Nothing could be further from the truth, but this has caused immense problems as legal and political systems try to put in place laws that would permit collections to be investigated. Secondly, there is a perception that NPs are “old hat” and that combinatorial chemical processes coupled to high-throughput screening has made NP investigation obsolete, not cutting edge! In the case of HTS plus combinatorial chemistry as a substitute for NP discovery, currently I know of only one approved drug in any disease that is a de novo combinatorial product and that is sorafenib. Combinatorial chemistry is absolutely magnificent for "lead optimization" but unless it uses focused libraries, a lot of which now closely resemble NPs in terms of their elemental composition, numbers of rings and presence of multiple chiral centres, they simply occupy space on a test plate.
Q. How do you get into the drug pipeline?
If it is our compound we will competitively licence the molecule for further development. This also occurs if it is not a patentable compound (such as Taxol) where no company would perform clinical trials. This compound was discovered under one of our earlier collection programs where we utilized the skills of
academic and non-profit chemists to isolate and identify NPs. The material was taken through Phase II clinical trials by NCI and collaborators and once it had shown activity in ovarian cancer in female patients, it was licensed to Bristol Myers Squibb.
Q. What highlights have you seen?
Obviously, I cannot go into compounds that are still in the early development pipeline, but Taxol is one highlight. A more recent one is the work that we did with Eisai America on Eribulin derived from a very potent marine sponge metabolite known as halichondrin B. We had to extract 1 metric tonne of the sponge to get 300 milligrams of hali B working in conjunction with New Zealand government scientists and academic chemists. It is now in Phase III. Another is an inhibitor of heat shock protein 90. When NCI intramural scientists showed that HSP 90 was inhibited by an old but well-known antiparasitic agent known as geldanamycin, NPB had the problem of finding a producing microbial culture and then generating over 3 kg of pure geldanamycin in order to permit other chemistry groups within DTP to produce what is now known as 17-allylamino-geldanamycin, which was licensed, together with other compounds and information to Kosan Pharmaceuticals (now part of BMS). This first signal transduction agent is currently in Phase III.
Q. Can traditional medicine help?
Provided the data is rigorous and not anecdotal, such information can lead us to areas that we have not investigated in the past. If multiple preparations are being assessed from the nominally same plant but from perhaps different areas, climates, time of year etc., then there must be adequate evidence of chemical content (say an HPLC fingerprint) and biological activity to compare with the active fingerprint. Sadly, this is lacking in a very large number of cases; faith is not a substitute for evidence under those conditions.
Q. What's the future of NP research?
Investigating NP chemical structures that are potent agents in your disease of choice will lead you to structures that are the products of aeons of experimentation and can be utilized to design simpler molecules with less toxicity and perhaps better pharmaceutical properties. Mother Nature has almost four billion years of evolution to practice her biological chemistry in designing molecules that interact with proteins. On an active coral reef, we find extremely potent agents that kill cells; hali B is one example, Yondelis from the tunicate E. turbinata another. I often joke that, on a coral reef, WMDs are alive and well.
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