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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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In the Pipeline

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September 19, 2008

Sunesis: No Substitutions Allowed?

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Posted by Derek

A colleague mentioned to me the other day that Sunesis Pharmaceuticals had let many of its remaining research staff go back during the summer – they’re battening down to try to get their main clinical candidate through for leukemia and ovarian cancer. That’s a common phase of life for a small company trying to go it alone. Clinical trials are expensive, and so are scientists, and sometimes a company finds that it can’t afford both at the same time. Amylin, to pick one example, went through so many cycles of that (starting in the mid-1990s) that I completely lost count.

The Sunesis news struck me, though, because if you go back a few years in the literature, they’re all over the place. The company was aggressively investigating (and promoting) a technique called “tethering” as a platform for drug discovery. Back around 2003, they were all over the journals with it.

Tethering was one of those neat ideas which seems to have been a lot of work to reduce to practice. It’s a variation, in its way, of another one of those techniques called Dynamic Combinatorial Chemistry. In DCC, you take a good-sized collection of compounds which can form reversible bonds with each other. Thiols (R-SH) have been used a lot, since they can form disulfides (R-SS-R), which can easily come apart and re-form with other thiols. In the presence of some target or template, such as the binding site of a protein, the idea is that any disulfide combination that manages to bind well will get enhanced in the final mixture, since it spends more time out of the swim of potential reactants. Comparing the product distribution with and without the target protein can point you to a potential lead structure to optimize. (You can also turn it around and make synthetic receptors (PDF) for molecules that you're interested in).

The idea behind tethering was, at least in one of its main variations, to introduce an extra thiol group into a target protein somewhere close to its active site. Then this mutant protein would be screening against a library of small molecules with thiol groups of their own, with the idea that if there was a binding site near that thiol that it would be found by preferential disulfide formation between it and some member of the screening library. Then came the second step. Normal, unmutated protein would be exposed to a mix of that preferred thiol and a library of other potential thiol coupling partners, in an attempt to find another preferred extension into the binding cavity. So this was basically a way to do DCC, but giving it a leg up by trying to make sure that there was a good amount of at least one thing that could bind to some relevant part of the target.

That tells you that standard from-the-ground-up DCC must have some difficulties, since if it worked as well as its concept you wouldn’t need to put your thumb on the scales like that. But I was never sure how well tethering worked, either. The company published numerous examples of it, but I don’t know if any of these compounds ever got anywhere (and indeed, I’m not at all sure that their current clinical candidate was discovered by this technique).

There are several places where things could break down. Making a mutant protein introduces some uncertainty, for starters. That SH group might not change things, or it might change them just enough so that the binding site you find doesn’t quite exist when you switch to the wild type. And any binding site you find in the first round isn’t necessarily a productive one – the original protein SH group was targeted to try to dangle out over the right part of the protein, but there are no guarantees about that. Past that, even if you get through the second round and find some new disulfide hits (no sure thing), they are, well. . .they’re disulfides. And those are poor bets for drugs.

That’s where the real weak point of DCC is in general, to my mind. Using reversible reactions gives you compounds with too much potential to fall apart, so the first thing you have to do is replace those bonds with something sturdier – and that’s not always easy, or even possible. There are very, very few clean substitutions available in the chemical world. Nothing’s quite like a nitrile except a nitrile, and there’s only one thing shaped exactly like a t-butyl group: another t-butyl. Likewise, the only thing that’s guaranteed to look and act like a disulfide is a disulfide. A two or three carbon chain replacement is the logical place to start, but that might be synthetically tricky, or (even more often) might turn out to be a completely different sort of compound once you’ve made it.

In the end, I think tethering turned out to be an excellent means to get some very interesting papers published in some good journals. (The publications have continued to this day). But beyond that, I’m not so sure. I’d be glad to hear from any ex-Sunesis people with other views. . .

Comments (23) + TrackBacks (0) | Category: Cancer | Drug Industry History


COMMENTS

1. Doug on September 19, 2008 9:30 AM writes...

The tethering method reminds me of some interesting methods using click chemistry. It's almost exactly the same idea except using click enabled compounds in place of the thiols. Is that method fairing any better, or is it too early to tell?

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2. Jose on September 19, 2008 10:08 AM writes...

Doug- the major advantage of click is that you form a nice, stable triazole instead of a PITA disulfide- that alone wins in a landslide.

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3. Kevin on September 19, 2008 11:04 AM writes...

Sunesis has laid off essentially all their research chemists.

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4. WC on September 19, 2008 11:39 AM writes...

"Tethering was one of those neat ideas which seems to have been a lot of work to reduce to practice."

That's an understatement IMO. We interviewed a candidate from Sunesis and I felt sorry for this person for having to do this "tethering" platform. It's a synthetic slog through molasses. Someone even suggested we try some of this technology. I couldn't have been any less enthused.

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5. JC on September 19, 2008 12:55 PM writes...

Seems to me that companies that use these fragment & tethering approaches (think Theravance also) have a knack for closing up shop.

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6. Fred on September 19, 2008 1:10 PM writes...

JC. DId youwork at Versicor in the 90's?

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7. Hap on September 19, 2008 1:13 PM writes...

I know it's whiny, but if a small company cuts most of its research staff before their drugs make it to market (or not), doesn't that make it even less desirable to work for them? I had assumed that the financial compensation for the higher risk and longer hours (I assume, but don't know) was the ability to reap profits when your efforts (or those of your company) succeed, by having equity in the company. Do the laid off people have any equity in what's left of their companies, or do only the management staff/founders have any? If the latter is true, the initial question would stand.

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8. DerekF on September 19, 2008 1:34 PM writes...

The compound furthest in trials, SNS-595, is in-licensed by Sunesis; as is their second compound, SNS-032 [info from Sunesis website].

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9. BioGuy on September 19, 2008 2:14 PM writes...

Hap, this is unfortunately the typical lifecycle for small drug discovery/development companies these days. A friend of mine likened it to a multi-stage rocket which has to shed sections if it has any hope of moving forward.
When you get laid off under these circumstances, you end up getting mostly screwed out of any potential future benefits. Assuming your 'risk compensation' package is composed of stock options, you'll have a few months to exercise any that have vested. By this time, you don't have much confidence in the company anymore and, having just lost your job, you may not be looking to spend money to buy stock in the company that just laid you off. Such is life in biotech...

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10. Cloud on September 19, 2008 2:23 PM writes...

@Hap- sometimes your stock options instantly vest if you are laid off in a mass layoff like this. However, in most cases you won't want to buy even if they are vested. What you're really gambling on is that your company will be one of the lucky few that makes it through without laying off all of their research staff.

In my opinion (I'm working at my 3rd biotech now), my salary is the compensation for the risk. The stock options are a lottery ticket. However, I never thought the job I held at a big company was all that secure, either.

The things that made me choose to leave my BigCo job and come back to biotech are the energy and team atmosphere that a good biotech can have. My current job is just more fun than my old one was. Of course, when a biotech job goes south, it goes south in a big way. I've been through that, too. But for me, the trade off is worth it.

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11. JC on September 19, 2008 4:02 PM writes...

Fred - Indeed. Is this Redhead Fred of the JC/SLAM/FRED triple threat?

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12. Cellbio on September 19, 2008 5:01 PM writes...

Years ago I went on a diligence trip to Sunesis to hear about the unique path for finding drugs which bound to previously unappreciated sites on target proteins. They showed us their ATP competitive kinase inhibitor program. I knew they were in trouble at that point.

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13. Fred on September 19, 2008 9:55 PM writes...

JC- Triple threat indeed. Good times. How do we get off this thread without giving out our info. to the world?

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14. Flying Dutchman of Biotech on September 20, 2008 12:39 AM writes...

I hear the Jim Wells, former SNS founder, convinced UCSF (he was recruited to be director of the Small Molecule Discovery Center) to invest a lot of money & manpower (postdocs & grad students) using the tethering ..."which uses precise, sophisticated matchmaking techniques, to improving the success rate of finding chemical compounds with the potential to become drugs...".

But most of the work is for Sunesis on the taxpayer's dime so it does not really matter that SNS has canned a big chunk of its research staff. The screening work will still go on.

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15. Tethered to death on September 20, 2008 6:51 AM writes...

I was at Sunesis in the very beginning. The problem with this concept is that these protein protein interactions are very weak. It typically takes many such weak interactions to bind the 2 molecules together. Imagining that the 2 "sides" of your compound are going to interact with the 2 sites on the proteins, AND do it strongly enough to make a difference, is a stretch, no pun intended, well maybe it was intended.

Then you have to consider that your compound must have this linear presentation to the protein in solution in order to span this bridge. Not curl up into some other conformation, that isn't shown in the "cartoon"

There never was any real iterative SAR around these compounds, at least when I was there.

Just a way for certain profs from places like Berkeley, to try and get in on an IPO back in the late 90's

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16. Fries With That? on September 20, 2008 10:51 AM writes...

Yes, Tethering and Fragment Screening live on in
Academia on the Taxpayer's dime.
Of course, as all the presentations and Magical Thinking claim, these methods are
far, far superior to traditional screening.
Just imagine, one fragment or tether compound
in a screen is equivalent to several thousand
old fashioned small molecules. Just think of the
time and effort you will save!

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17. Flying Dutchman of Biotech on September 20, 2008 11:58 AM writes...

I really miss the wild, heady days of biotech back in the '80s and early '90s when VCs would fund companies with any crackpot idea, no questions or due diligence needed. Remember "Massively Parallel Signature Sequencing" from Lynx or phage library panning over at Affymax? How about the old retroviral display that Rigel touted in its early days before dumping it for normal HTS? Tethering technology as used by SNS will end up in the "what were they thinking?" dumpster if it already hasn't.

But by then that big boys would have made off richly while we scientist types end up working at Mickey D's.

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18. JGault on September 20, 2008 1:46 PM writes...

We worked with sunesus on a project that started as a tetherng project which then morphed into a more traditional appoach. Like many of the new DD technology companies with new innovative ways of finding leads they all eventualy learn ( Usually the hard way) that finding leads is not what is hard about drug discovery. I remember specifically having long dinner conversations with certain Berkeley Profs on his subject and getting the feeling the message never relly sinks in (although I think they clearly get it, they also know where thier butter comes from, and unfortunately selling the government on the idea that pharma doesn't know what they are doing is not getting harder). To get an idea of how these technologies always seem to attract start-up funds just think of your high level big pharma MBA managers who always want "outside the box" thinking. The thing they never seem to realize is the box that leads to successful drugs is orders of magnitude smaller than the stratispheric dimensions of the space of stupid (or perhaps just misdirected) ideas. I know people very high up in Sunesus research and know that they had a pretty clear head about the chances of success if they stuck solely to the tethering technology, unfortunately in this case the boat just did not turn fast enough.

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19. Facts on September 20, 2008 2:32 PM writes...

Tethering was Wells brain child and baby and as CSO he would never give it up

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20. Fries With That on September 20, 2008 5:08 PM writes...

A lot of these founders (mostly biologists) who don't understand a thing about chemistry, latch onto some sexy idea they think will land them the Nobel Prize, so they never let it go.

More time and effort is put into
the PowerPoint presentations
and self-promotion rather than
the science and business of developing
an effective therapeutic.

They tend to surround themselves with yes men and
women, and any one who disagrees is soon out of
job.

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21. dlib on September 20, 2008 7:40 PM writes...

I was trained in the old fashioned art of pharmacology...( it's called all sorts of new fangled names now ;-) My profs spent time with the indians of the amazons ( really ). I had a concept for a new way to do something very old...understand the thermodynamics of binding. Not too sexy, but very useful ( calorimetry ). In fact it had the potential to have fast enough responses to get the frequency distribution of the heat capacity function. You guys know how important that is right?? I've given talks blah blah...today, it's an unfundable technology -- your industry is paralyzed. Thankfully I make a living in the Semiconductor industry ( I was employee #10 -- got bought last year for $270M ). Never would have happened in Biotech. I feel sad since the industry I'm in I feel is souless.. Oh well. Good luck. ( oh I remember why I posted this ) one of the guys I spoke to was Jim Wells supposed to give a talk there but never materialized.

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22. DrSnowboard on September 21, 2008 2:42 PM writes...

re: tethered to death,
Back in Derek's comments is the phrase inhibiting protein -protein interactions is "trying to stop two elephants touching, by taping a grain of rice to one them." Thought that was pretty apt, wish I'd said it.

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23. Not So Fast on September 23, 2008 6:09 PM writes...

Flying Dutchman, your assertion is not accurate. The work Jim Wells continues at UCSF is a spin-out of an application he conceived of while CSO at Sunesis, but it's a more "academic" problem. He's doing this because he wants to explore the science, and what he finds does not revert back to Sunesis, "on the taxpayer's dime" or otherwise.

Also, having worked with Jim at Sunesis from the start, I can tell you that he did believe (rightly or wrongly) down to the very fiber of his being in the science that he was promoting. For Jim it was not about self-promotion, although his failings for inexperience or a lack of perspective were genuine as well.

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