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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 8, 2006

A Natural Wonder Drug - Now What?

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Posted by Derek

So, let's say that some jungle-extract natural product has shown good activity in some drug screens. What next?

The first thing to do is define "good activity". Screens can be done at several levels. The most abstract is against a purified protein (enzyme inhibition, for example), and that can be a long way from anything useful in a living system. You'd get excited if you have activity against an enzyme that a lot of people are interested in but no one's been able to get good activity against - protein tyrosine phosphatase 1B, for example, a fine diabetes target that's evaded all attempts so far at useful small-molecule inhibition.

A more stringent test is against living cells. Activity there shows you that you at least can deal with cell membranes (penetrating them or hitting targets on their surface) and that you can get the desired effect in the presence of all the other potential binding sites that a living system presents. Cancer assays are often done with living tumor cells, with the readout being slowed growth or outright cell death. (That latter one isn't as good as it might sound, since most things that will kill cancerous cells will kill every other kind of cell, too).

But let's assume that this natural product has shown something that's really worth following up. You're going to need more of it for animal models and toxicity testing. Now comes a tough decision: make the compound, or extract it? The former is often out of the question, since many of the structures we're talking about are so complex. Academic groups make them, of course, for the sheer challenge of it, and often talk about how their routes have opened up new possibilities for analogs of the original compound. But how often does that really happen? No one's going to do med-chem analoging in the context of a thirty-step synthesis.

The back-to-nature option isn't always available, either. Most natural products are found in such low concentation that insane amounts of the source material would be needed. In other cases, particularly with marine natural products, the source organism may have disappeared from its original collection site over the years. Some of these things have never been found again.

The most successful natural product drugs have been those that have a high-volume plant source somewhere in their pipeline. The Vinca alkaloids, for example, come from the fast-growing Madagascar periwinkle. (You could say the same thing about opium and cocaine, too, I guess, which have been successful in their way). You can't always find a good source of the final compound, though.

The next best thing is to find an advanced intermediate that a plant produces in quantity. That's the foundation for the modern steroid industry - it turned out that you could have Mexican yams make most of the steroid backbone for you, which is a wild story that's been told many times. A more recent example is taxol. Extracting the final compound from the Pacific yew tree just wasn't feasible on scale, not least because it was found in the bark and couldn't be obtained without killing the trees. Folks were looking at a yield of about a half-gram of drug per forty-foot tree - mind you, that's still easier than making the compound from scratch. But an advanced intermediate could be extracted from the needles, and Holton's group worked out a synthetic route from it.

Actually, those semisynthetic route might be the best overall, because it gives you a handle to generate analogs (the way the total synthesis routes do, in theory). Natural products are rarely given the kind of exhaustive structure-activity workout that smaller man-made molecues get - or if they do get one, it takes years to slowly work through the possibilities. You won't be able to ring all the changes based on what you get from the plant, but it's better than nothing. Taxol, for example, has had a great deal of work done on it, mostly in attempts to make the damn stuff more soluble. As it is, it has to be dosed in a vehicle that's almost worse than the drug for toxicity. That's a cruel trick of Nature, all right - insoluble compounds are something we can make on our own.

Comments (17) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. Abel Pharmboy on May 9, 2006 5:06 AM writes...

Since you mentioned Jon Clardy the other day, I might also add that his approach to cloning genes expressing biosynthetic enzymes for a given natural product is another tactic. In fact, I believe that one of the statins, pravastatin perhaps, is made entirely biosynthetically from a culturable fungus whose product is then fed to an engineered bacterium. Natural product SAR used to initially be done by feeding one's new wonder drug to a series of ATCC bacterial species to make semi-synthetic analogs (no offense intended to chemists like you Derek).

Because I have to sell my field to grant reviewers, I've made a whole table of natural products that are used in FDA-approved formulations as the naturally-occurring compound. No surprise that most are intravenously-administered antibiotics and antitumor agents, mostly for the solubility (and metabolism) reasons you describe - these things evolved to exist in bugs and plants up to a certain solubility product and we exceed this when making them for human use. Co-solutes, albumin, liposomes, etc. and, of course, semisynthesis still make this viable, though.

Finally, since you mentioned Mexican yams and diosgenin, it amazes me how alternative medicine hucksters use the story to sell wild yam extract misleadingly as a source of human hormones. The body can't do a dang thing to diosgenin except glucuronidate it and pee/poop it out - to make human bioactive steroids from this stuff, you need a chemist!

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2. Anon on May 9, 2006 5:37 AM writes...

An alternative view from Science here.

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3. Rob Cyran on May 9, 2006 7:18 AM writes...

Two thoughts:
- Could a rebirth of finding compounds from natural sources might help solve pharma's recent problems with finding drugs? Seems more than coincidence that the number of drugs dropped when high-throughput methods became widely used in labs. (Any opinions Derek?)

-There's probably a cultural bias against finding new drugs from biological sources at big pharma. My background isn't in pharma, but I know it's easier to get funding to do incremental research on a known topic than a new topic. Since drugs extracted from say, tropical sea slugs, are likely to work on completely new pathways (I think)than existing drugs, big pharma will probably shy away from researching them. Considering the pharma industry was built on high-risk, high payoff ideas, this strikes me as a mistake.

PS- take a look at Pharmamar, a Spanish company that is trying to find new drugs from marine sources. Kind of interesting to see if they can make it work.

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4. RKN on May 9, 2006 7:20 AM writes...

Natural products are rarely given the kind of exhaustive structure-activity workout that smaller man-made molecues get - or if they do get one, it takes years to slowly work through the possibilities.

I hope to be working with a relatively new compound in our lab which is a synthetic derivative of a plant triterpenoid. It's an anti-inflammatory drug, but also it's been shown to have a very strong apoptotic effect on a number of cancer cell lines, in vitro, with strikingly low cytotoxicity. I know these are a dime a dozen in vitro, but what's interesting about these is that the man-made derivatives are substantially more effective than the native compound, and in [nM] quantities. 'Tis amazing what merely changing the stereochemistry of a functional group can do.

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5. SP on May 9, 2006 7:22 AM writes...

Holton extracted quite a bit of cash from the needles too- what is it, $220 million or so? How often does a synthetic academic group hit that kind of jackpot?

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6. MikeT on May 9, 2006 7:47 AM writes...

Hey, I got a chemistry degree from Florida State University. I think the chemistry department should be ranked higher. There really is some good research going on there, very hard workers.

Holton did make a lot of money, but the majority went to the university and then he donated a lot to a new chemistry building. That's a whole other story.

The only problem is FSU doesn't do much for their graduates to get jobs, but they can get you into grad school. The southeast isn't much of a hot spot for pharma.

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7. John Johnson on May 9, 2006 8:48 AM writes...

MikeT - point your car north on I-95 for about 12 hours. When you get to I-40, head west for about 45 minutes. Stop in RTP.

Bring a suit. You can almost walk door to door.

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8. Mark on May 9, 2006 10:33 AM writes...

John J:

when is the last time you looked for a good synthesis position in RTP. It used to be as you described--and the area is a great place to settle down.

But for new PhD's -- I am afraid RTP is not the gold mine it was (or could be). I should know.

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9. Drew on May 9, 2006 1:29 PM writes...

Rob- Several big pharmas had research stations in Australia and elsewhere in the Pacific in the 70's and 80's, trying to find leads. Very slow, costly, and hard to justify to the bean counters. Academics (Phil Crews, Molinski, Pettit, etc) have the time and cheap labor to grind through it all. Even still, I suspect their hit rate is very low.

SP- AFAIK, Holton is essentially the only academic to hit a jackpot like that. There are some smaller deals (ten thousands to maybe a million), but Taxol is in a catagory all its own.

Permalink to Comment

10. Derek Lowe on May 9, 2006 2:04 PM writes...

Ah, but there's Dennis Liotta, too. . .

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11. nigel on May 9, 2006 2:41 PM writes...

There's also Corey, apparently, with a recipe for shikimic acid -

http://www.newscientist.com/article/dn9107-way-to-mass-produce-key-bird-flu-drug-revealed.html

- but he's giving it away free.

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12. Ryan K. on May 9, 2006 3:08 PM writes...

Ted Molinski is a nice... well, let's just say very hard working and very intelligent guy. He doesn't get enough good talent or funding coming through his lab though. With a few notable exceptions(you know who you are mako!).

Natural Products labs can be very funny places sometimes. After accidentally spilling a NP solution on the floor, I have seen people literally trying to extract the linolium floor to recover it.

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13. RET on May 9, 2006 3:54 PM writes...

Taxol is not a very good example. It is doubtful that plant secondary metabolites are produced for distribution or as a defense mechanism through transport. Thus, water solubility was not worked into the evolutionary process. Moreover, despite a lot of synthetic work, taxol was far from exhaustively studied by SAR.

Natural products from microorganisms, on the other hand, are made to interact with competitors in the environment; water-soluble but greasy-enough to pass through membranes. The epothilones are an excellent example. Despite taking at least 20 steps to prepare academic labs and several major pharmaceutical companies prepared 1000s of analogues. Potentially, the first complex natural product "complete" SAR. Schering and Kosan have purely synthetic analogues in clinical trials. While BMS and Kosan have semisynthetic and naturally-occurring compounds also in trials.

Bob Vince (Minnesota) is a third example; $.

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14. secret milkshake on May 9, 2006 6:50 PM writes...

Most of the money in pharma research is not spent in actual research. The marketing and promotion of existing drugs in a company like Pfizer costs several times more than all clinical and preclinical expenses combined. Chemistry and biology research is much cheaper than clinical trials - but it is still expensive with the enormous overhead in a bureaucratic behemont. Add all the bonuses of execs in the "research" and you will understand why companies usualy do not let chemists work on natural products - they would have to employ too many. Besides, one can wait for academic groups to produce goodies, then licence in.

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15. Doug on May 9, 2006 10:10 PM writes...

Fortunately, they eventaully developed partial synthesis of paclitaxel (Taxol) from yew needles, (which can be harvested without killing the trees) or can be grown in plantations. Unfortunately, they wontonly killed hundreds of thousands of rare yew trees from old growth forests that also provide habitat for threatened spotted owls and Pacific salmon. "Wild nature" should be used for resarch and possibly clinical trials but commercial demand must be met with synthesized, or at least "domesticated," sources.

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16. MikeT on May 10, 2006 10:58 AM writes...

@John Johnson

Do you currently work up there? I'll send you my resume. I tried to get a job at RTP when I was graduating, but I could barely get a response.

Permalink to Comment

17. Jane Yao on July 17, 2012 6:38 PM writes...

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We (usahealthresource.com) provide over 12,000 non-commercially available compounds and fractions obtained by column separation of worldwide chemically untapped natural products.

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