David Newman is Chief at the Natural Products Branch, Developmental Therapeutics Program, DCTD, at the National Cancer Institutes in Frederick, Maryland, USA. I interviewed him for Issue 1 of a new quarterly newsletter called Chemistry Matters in Pharma.
This is Part I of the unabridged transcript of that interview in which Dr Newman told me of the ins and outs of natural product chemistry and how it can lead to new pharmaceuticals for a wide range of diseases.
Q. What is your approach to natural products?
A. The remit of the natural products branch (NPB) is to find novel leads to agents that may be of utility as antitumor 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, World-wide in the case of the plants and marine organisms, and predominately in the US for microbes, though before the Convention on Biodiversity, we did collect microbes in various places outside of the US and its territories. Currently we are collecting microbes and marine invertebrates.
All materials are brought to NCI-Frederick at the US Army’s Fort Detrick in Northern Maryland where we have the necessary equipment to “convert” the plants and marine invertebrates into water-based and organic-based extracts, and the ability to isolate, purify and then ferment, microbes before their fermentation broths are also extracted. We currently have over 140K plant, 30K marine and roughly 30K microbial extracts arrayed in test plates (dry) and with bottles containing more of the extracts (amounting to roughly 650K bottles/vials) all stored at minus 20o C.
Materials are tested by NCI in its 60 human cell line screening system and also made available under very strict guidelines to researchers both inside of the NIH and to academic, non-profit and small and large businesses world-wide with very strict guidelines that require that any organization discovering a lead that ultimately is commercialized, MUST work with the country of origin in its commercialization. In the event that NCI/NIH scientists find a lead of interest that is patented in the name of DHHS (the Department of Health and Human Services, NIH’s parent organization), then any organization that licences that patent MUST, within one year produce an agreement with the country of origin that covers their benefits from the licence. If not provided, the licence is pulled. We call this the “source country commitment” and in a less-refined form, it was in force three years before the Convention on Biodiversity.
Q. What day-to-day chemistry is your team engaged in to achieve those goals?
A. 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. All forms of chromatographic isolations are used and in some cases, we will go back to older techniques because they “work”, particularly when we are dealing with charged molecules. Access to standard spectroscopic instruments is also 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?
A. 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 antitumor agents. There is another Program, known by the acronym CTEP (Clinical Trials Evaluation Program), part of whose job is to take molecules that we “produce” and conduct clinical trials on them.
We will accept molecules from any source either from our own work or from outside and carry them through the system(s) 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. We consider this to be routine assessments. So the NP compounds definitely mesh with NCI’s aims.
Q. How do you assess the natural products you find in terms of toxicity and synthesis issues? What’s your group’s remit on those aspects of the work?
A. 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 that have “cytotoxicity” above a certain nominal level then proceed to the regular 5 dose 60 cell line screen. An assessment is then made of the “patterns of activity” in the full screen and a decision is then made as to dropping it or continuing.
Because we currently have the capacity in our in vivo testing, we have actually gone back many years in concept and actually test the crude extract (after a quick toxicity test) in the hollow fibre (HF) assay in nude mice. If we find activity, then we will move to very specific xenograft (XG) studies using cell lines that either showed activity in the HF assay or sometimes, will go with a specific cell line in XGs due to its activity in the 60 cell line. If the XG is “active” in protecting against the effects of the tumor with respect to control mice, then we will “dereplicate” chemically and find out what the “active component(s) are.
Although this may look like going backwards in time to the early 1960s, what it has permitted us to find, are synergistic mixtures of known compounds that are active in the XG assay(s) at levels well below what the pure compounds show activity at, and in one particular case, one of the compounds has never shown activity, only very significant toxicity as the individual compound. The Therapeutic Index (TI) of that particular compound is almost equivalent to 1 as a single agent!
Q. How do you take this research into the drug pipeline and thence clinical trials and ultimately the pharma market?
A. DTP or CTEP will accept suitable molecules from any source either from our own work or from outside and carry them through the system(s) 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. We consider this to be routine assessments. So the NP compounds definitely mesh with NCI’s aims. (from answer to Q3 above).
In addition to these trials, we will if it is our compound (meaning our patent), 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 natural products. 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 licenced to Bristol Myers Squibb under a competitive Cooperative Research and Development Agreement (CRADA) that included requirements for further clinical trials and methods of obtaining the compound from natural sources. This is a much too long a story to go into in a Q & A session but it has been described in a lot of articles and books.
Part II of my interview with David J Newman will appear on Sciencebase.com soon.
You can read more about Dr Newman’s perspective on natural products and how it is not so much old school as the new dope:
Newman, D. (2008). Natural Products as Leads to Potential Drugs: An Old Process or the New Hope for Drug Discovery? Journal of Medicinal Chemistry, 51 (9), 2589-2599 DOI: 10.1021/jm0704090
Check out the free associated newsletter Pharma Matters Reports with whom I’m working with Thomson Reuters.