Interview with David J Newman (Pt. II)

This is Part II of the unabridged transcript of an interview with Dr David Newman, Chief at the Natural Products Branch of the NCI in Maryland. The interview was conducted for a new quarterly newsletter – Chemistry Matters. You can read Part I in which Dr Newman discussed how natural products can lead to novel leads for pharmaceuticals.

In Part II, he tells us about the highlights, the lows, and the future of natural product research in the pharmaceutical drug discovery process.

Q. What specific highlights have there been? Any recent breakthrough drugs?

A. To answer the second part of the question first. For obvious reasons, I cannot go into compounds that are still in the early development pipeline as I can only provide information that is in the “public domain” due to IP issues.

The story of Taxol® above is one. A more recent one is the work that we did with Eisai America on the evaluation of a compound that now is known as Eribulin that though made by Eisai chemists, is 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 in NZ. Once we had the material, we were able to perform preclinical studies with both it (the NP) and the Eisai compound, then perform preclinical studies on eribulin (as it had a much better TI than the NP to my chagrin!) and ultimately “honcho” it through the DTP system in conjunction with Eisai scientists to Phase I clinical trials under CTEP auspices. It is now in Phase III.

Another is an inhibitor of the protein chaperone known as heat shock protein 90 HSP90). 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 kilograms of pure geldanamycin in order to permit other chemistry groups within DTP to produce what is now known as 17-allylamino-geldanamycin, which was licenced, together with other compounds / information to the then Kosan Pharmaceuticals (now part of Bristol Myers Squibb) where it is currently in Phase III trials. This was the first “signal transduction agent” to go into clinical trials.

Q. What challenges do you face in general?

A. Two in particular. Access to countries in order to collect materials for investigation and the 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 first case, this is due to the fact that the US, though it signed the Convention on Biodiversity (CBD) the treaty was never ratified by the US Senate, a constitutional requirement for all foreign treaties. NCI luckily had realized that formalized methods of recompense to countries that permitted us to collect was something that was lacking, and so in the late 1980s, devised the NCI’s Letter of Collection (LoC), which was first signed with the Malagasy Republic in 1990, three years before Rio. Although monetary royalties cannot be part of such an agreement due to US Law (such a statement would “encumber any future invention” as the act of collection is not a patentable process), methods such as training and aid in development of compounds is permitted. NCI has formal LoCs with over 20 countries and if a country permits us to collect, even if there is no formal LoC in place, the tenets (in particular the source country commitment, see below) are observed.

What has also occurred is what my old Chief (Gordon Cragg) and I have called the “Myth of Green Gold”, where totally unrealistic expectations have been foistered 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 it, and other ideas as to what is required to actually develop a drug from an extract, has caused immense problems as legal and political systems try to put in place laws that would permit collections to be investigated.

Without naming the countries involved, I will give a couple of examples. One country has in their law the statement that any agreement with an offshore organization means a “commercial agreement must be in place” even if it is with NCI for example. This country does not have the capability to develop a drug due to lack of infrastructure.

In another case, a state within a country currently does not permit materials to be worked on in other states in the same country, even though they have neither the population nor infrastructure to perform the necessary work to discover and develop a NP derived compound as a drug candidate….”it must be done in state X”…….

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, a kinase inhibitor. 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 centers, they simply “occupy space on a test plate”.

Plus what has become quite evident is that assaying against isolated enzymes gives rise to a very large number of “hits” and very few “leads” and even less “leads” that have activity either in cellulo or in vivo, and if they do, the loss in potency is orders of magnitude from in vitro to in vivo. Even more troubling is the recent papers that show that a significant number of “hits” are in fact artifacts of the assays (usually due to physical interference, not genuine activity).

Q. How can traditional medicine (Chinese/Ayurvedic etc) help in the search for novel leads?

A Provided the data is rigorous and not anecdotal, such information can lead us to areas that we have not investigated in the past. What do I mean by rigorous? The plant(s) {and they are almost all plant-derived} must have been identified taxonomically, the part(s) of the plant(s) used must be identified and shown to only be that particular part or parts from the correct plant. Most importantly, the growth and / or cultivation of the plant must have been defined according to one of the recognized herbals (often what is known as the “Emperor’s Red Book” in Traditional Chinese Medicine {TCM}) and the plant(s) provided be harvested at the time / climatic conditions / storage as defined above.

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 / activity. This is the equivalent of a certificate of analysis (CoA) that is required for regular medications and / or their contents.

Sadly, in a very large number of cases, parts, if not most, of the “requirements” above are lacking in a very large number of the preparations and reports; faith is not a substitute for evidence under those conditions.

Q. What future do you see for natural products research?

A. For obvious reasons, I am biased. However, what Mother Nature has is almost 4 Billion years of evolution to practice her “biological chemistry” and in designing molecules that interact with proteins. Due to the massive commonalities shown by comparative genomics between Homo sapiens and microbes, compounds from such organisms may and often do, interact with human proteins that are paralogs of those found in lower organisms. Why do I say microbes? Because in a large number of cases, the compounds that we find may well be the product(s) of interactions between microbes and their hosts such as marine invertebrates or plants and they were probably designed as defensive agents to stop predators.

This is almost certainly the case with marine-sourced materials where the nominal producing organism is an invertebrate as they have to filter-feed and to do that, they must have a “toe-hold” on a suitable surface. Since they do not have teeth or claws, their defences are chemical in nature. I often joke that WMDs are alive and well on an active coral reef and we are finding extremely potent agents that kill cells from such areas (halichondrin B above is one example, Yondelis from the tunicate E. turbinata is another).

Thus investigation of the chemical structures of NPs that are potent agents in “your disease of choice” will lead you to structures that are the products of aeons of experimentation and that can be utilized to design simpler molecules with less toxicity and perhaps better pharmaceutical properties. Certainly when one bears in mind that 70+% of all approved antitumor drugs World Wide since the 1930s are natural products, modified natural products, contain the natural product pharmacophore or are simply spatial mimics of NPS such as ATP (the kinase inhibitors), then the utility of NPs is proven as leads to drug candidates.

Are NPs themselves going to be drugs in their own right? Not necessarily, but with the advent of modern synthetic processes, modifications will be.

Research Blogging IconNewman, 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.

Author: bob投注平台

Award-winning freelance science writer, author of Deceived Wisdom. Sharp-shooting photographer and wannabe rockstar.