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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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February 12, 2006

Kinase Inhibitors: Doomed From the Start?

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Posted by Derek

Gilbert Rishton, ex-Amgen and now with an Alzheimer's institute in academia, sent along this paper the other day (PDF) which is worth a look for anyone in our business. Titled "Failure and Success in Modern Drug Discovery", it's a very opinionated look at the subject.

I sent it around in my department at the Wonder Drug Factory, and reactions were strong and all over the map. Several people found it right on target (and rather refreshing) while others were more reserved or outright hostile. One of the more controversial sections contends that drug discovery efforts are seriously overweighted in kinase inhibitors because the compounds are likely to be intrinsically toxic via general signal transduction inhibition in non-target organs. I'm pretty sure that I buy the first part, but I'm not sure about the second.

I think that the big problem in kinase inhibition is that we don't understand the details of the biochemical pathways anywhere near well enough in most cases. So we look at the state of the art and say "Well, it's clear that XYZ kinase is a key player in this pathway, so let's go inhibit it". But if we do, likely as not we find that there are so many compensating mechanisms that inhibiting XYZ hardly does anything. But that's if we have a selective compound, mind you. Most of the time we're hitting enough other kinases that it's impossible to say just what's causing any particular in vivo effect.

Anyway, take a look at the article and feel free to post comments that you might have. There's something in it to offend almost everyone. I'll be returning to some of its themes in later posts. . .

Comments (16) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. bmorse on February 12, 2006 11:41 PM writes...

Toxicity is often raised as an issue with kinase inhibitors, but I think the available evidence indicates that it will not be as big of a problem as this author suggests. My understanding from talking to oncologists, e.g., is that the types of 'toxicity' and 'side effects' observed with kinase inhibitors is not even worth mentioning when compared to many of the chemotherapeutic agents. I believe the antibodies are even less toxic than the small molecule inhibitors. As for efficacy, I that it's hard to argue with the success of the kinase inhibitors (Avastin, Gleevec, Sutent, Sorafenib, Tarceva, Herceptin) in treating many cancers, especially compared to the alternative.

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2. Peter Ellis on February 13, 2006 4:58 AM writes...

>the compounds are likely to be intrinsically toxic
>via general signal transduction inhibition in
>non-target organs

You disagree with this, but then say:

>Most of the time we're hitting enough other kinases
>that it's impossible to say just what's causing any
>particular in vivo effect

Doesn't the second pretty much imply the first?

I know that there are non-selective drugs that are also non-toxic, but it strikes me that throwing a lot of spanners into unknown works is a surefire recipe for *some* toxicity, or at least great risk of it...

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3. Derek Lowe on February 13, 2006 7:19 AM writes...

Peter, you've put your finger on the source of my ambivalence. Bmorse above is right that the antibodies are less toxic in this area, but that's probably because they're so much more selective. But they're so selective that they only work against a very limited range of tumors, thus the current generation of small molecules.

For a long time, companies avoided developing broad-spectrum kinase inhibitors just because of worries about this kind of toxicity. But with Bayer's Nexavar and Pfizer (Sugen's) Sutent, we'll have a chance to see how they really perform.

My take is that Rishton's about half right. These compounds are going to show some toxicity, but against thinks like malignant melanoma, who cares? There are enough severe (and poorly treated) kinds of cancer to leave a pretty large market. But is it large enough for the number of compounds that are in development? I wish I knew.

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4. Doc Bushwell on February 13, 2006 9:47 AM writes...

Toxicity may be less of a concern with oncologic kinases, but the MAP kinase inhibitor programs directed toward inflammation call for a more stringent tox profile. Coming up with an ATP-competitive protein kinase inhibitor with a low nanomolar Ki, lousy physical properties, and horrendous PK is not so hard, but ferreting out the impact on baroque signaling pathways is the big challenge. A friend (med.chemist who was the head of kinase chemistry at our former mutual place of employment) and I used to lament over martinis at Friday happy hour that an endless array of biochemical assays for a gazillion isolated kinases, aimed toward evaluation of specifity, was nearly next to useless. Our Grey Goose fueled discussions invariably concluded with "Hell with it! Just do a 2 week tox study," providing that the kinase inhibitor under giddy scrutiny had some semblance of reasonable PK.

Rishton's assessment of proteases as "high probability of success" in the small molecule tractability classification is hilarious. Ask any battle scarred pharma veteran of the protease wars, and I am one of them, about "tractability." So-called druggable protease inhibitors more often than not have horrendous physical properties and PK. Peptidomimetics anyone? Sure, there are exceptions, but I am hestitant to classify protease inhibitors as "high probability." I would say that peptidases represent more tractable targets.

He also demonstrates an incredibly naive view of in vitro mechanistic biochemistry. All too often, the hits from high throughput screening are characterized in half-baked ways by biologists with little understanding of mechanism. I can't begin to count the number of times I have advised my colleagues in biology that they are forcing fits to incredibly crappy data in hopes of deriving an IC50, which in turn gets dumped into a database with no question. Even worse, they apply the Cheng-Prusoff equation to calculate a Ki when they have not a clue as to the inhibition mechanism. Fortunately, the biologists are willing to be educated so I'm seeing improvements. Furthermore, the ability to delve into assay connectivity, i.e., from the in vitro biochemical assay to cell based assays to pharmacokinetics and pharmacodynamics, is critical. I don't know about the Wonder Drug Company, but in my milieu, that's a concept we have to hit on again and again.

Rishton's horror at covalent modifiers is pretty amusing, and frankly, rather antiquated. For one thing, "covalent" does not always mean "irreversible." He would have done well to check out David Swinney's article, "Biochemical mechanisms of drug action: what does it take for success?" in Nature Reviews Drug Discovery 3, 801-808 (01 Sep 2004). Some of Swinney's stuff is oversimplified, but he makes a good point: there's a bigger world out there than non-covalent reversibly binding inhibitors.

My apologies for this lengthy screed, but yes, Rishton's article hit a nerve or two. You're right: there's something to offend everyone. I'll pass it around to my grizzled old veteran colleagues, present and past, and then break out the vodka, ice and cocktail shaker.

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5. PandaFan on February 13, 2006 10:38 AM writes...

He can't seem to get his dates right either; Gleevec first approval was in May 2001, not the "mid-1990's"

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6. LNT on February 13, 2006 11:03 AM writes...

Two questions:
1.) What about kinase inhibitors for non-cancer indications?
2.) What are the qualifications of the person writing this article and where was it published? From what I can tell, he works at Cal State University -- a far cry from having "real life" pharma experience. And I certainly don't recognize the journal entitled "Medicinal Chemistry". It's not even listed on our company library catalog!

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7. LNT on February 13, 2006 11:21 AM writes...

Rishton bashes the productivity of pharmaceutical R&D as being "unsustainable". Do you guys agree with this? I just took a quick look at Wyeth's SEC filings and observed the following:
Net Revenue (2003) - 16 billion
Cost of goods sold - 4.6 billion
Sales and administrative - 5.5 billion
R&D - 2.1 billion.

As a percentage of revenue, R&D expenses are not terribly high. I don't think R&D expenses are going to kill the industry. It only accounts for about 15% of revenue. Sales and administrative, however, is another story...

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8. Derek Lowe on February 13, 2006 11:43 AM writes...

Rishton's just about the same age as I am, with the same number of years of experience in the industry. It can be dangerous age, I can tell you, since it's the first period in which you feel able to make sweeping pronouncements. That doesn't mean that they're wrong, but it's a new sensation to be able to do it.

He was in on the ground floor of Amgen's small molecule efforts, which gives him a different perspective (and seems to have also given him the chance to move over into academia).

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9. Derek Jeter on February 13, 2006 5:58 PM writes...

While the paper was heading toward interesting, Rishton lost me when he said that there is no probability of success for small molecule inhibitors of growth factor receptors. Has he heard of Tarceva or Sutent?

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10. Palo on February 13, 2006 6:10 PM writes...

Sweeping generalizations like Rishton's are of course bound to find easy criticism. I guess when Rishton talks of "no probability" of success of covalent-acting compounds, or small molecule inhibitors of growth factor receptors, he's getting at long-term strategies for success while making money for the companies, notwithstanding isolated successes.
The part I found interesting was his emphasis on the role-model success of small biotech. I personally find this 'success' a bit misleading. Most biotech are, for the most part, spin-offs of successful research programs at NIH or universities, and it is highly biased to look at their accomplishments without taking into account that they've been in fact pre-selected in their success: the unsuccessful research at a university, by definition, doesn't result in a biotech start-up. Big Pharma companies on the other hand cannot survive on only one successful drug, and they need creative ways to diversify.
A touchy underlying issue in all this is the role of federal-funded research in the development of novel drugs. Inadvertently (or not) Rishton might be giving fodder to critics that picture big Pharma as inefficient and less creative.

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11. Sebastian Holsclaw on February 14, 2006 2:32 AM writes...

"The part I found interesting was his emphasis on the role-model success of small biotech. I personally find this 'success' a bit misleading. Most biotech are, for the most part, spin-offs of successful research programs at NIH or universities, and it is highly biased to look at their accomplishments without taking into account that they've been in fact pre-selected in their success: the unsuccessful research at a university, by definition, doesn't result in a biotech start-up."

Yikes. I live in San Diego, one of the biotech 'zones' and have many friends who regularly work for biotech start-ups. They have a huge failure rate. It is a classic mistake of economic analysis to look at the successes without looking at the failures. Rishton does this a little bit in his paper, but Palo you do so even more. Biotech research is an incredibly risky undertaking. Unsuccessful research at a university doesn't turn into a biotech firm, but neither does initially promising work at a university mean that the biotech follow through will lead anywhere. Both are very important parts of a long winnowing system which hopefully ends up in useful therapies--but which unfortunately has an almost unimaginable amount of fruitless work tied into it.

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12. Derek Lowe on February 14, 2006 8:02 AM writes...

Derek J., the drugs you mention are all kinase inhibitors at heart. They act on growth factor receptors by inhibiting kinases necessary for their activation. I think that Rishton is talking about direct ligand-binding modes for a small molecule, which is indeed very likely to be doomed. Think "small-molecule isostere for insulin" and shudder.

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13. Palo on February 14, 2006 11:26 AM writes...

Sebastian,
It would be very interesting to get the statistics on failure for compounds initiated at start-ups vs. those started from scratch at big Pharma. Of course there's a lot of failure, that's the nature of the business. That doesn't mean they don't, by definition, start on more promising ground. My point was that the first basic research screening for new drugs was already done for start-ups, not so at big companies...

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14. PS on February 14, 2006 12:18 PM writes...

I dont have to write a review article to tell you that targetting cell surface receptors with small moelcules, protein or antibodies should have a much greater chance of success. Quite obviously, getting an exogenous chemical into the right tissue-cellular-subcellular compartment and then exerting a useful pharmacological response, is going to have a higher failure rate.

Has anyone ever compared location of the target ie cell membrane/cytoplasm/nucleus vs probablity of success in a drug discovery program?

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15. Anonymous on February 14, 2006 11:52 PM writes...

Sebastian Holsclaw wrote "Yikes. I live in San Diego, one of the biotech 'zones' and have many friends who regularly work for biotech start-ups. They have a huge failure rate. It is a classic mistake of economic analysis to look at the successes without looking at the failures."

Come on guys, this whole discussion sounds like a bunch of big pharma whining. The last time I checked, big pharma was not restricted from collaborating with academic labs or not allowed to file gene patents.

There may be a lot of biotech companies that go under but I dont see how that is any different from the large number of resource intensive drug discovery projects that do not yield a clinial candidate. Most start up biotechs raise and spend a few million before they go bust, but how many millions/billions does big pharma spend every year with nothing to show at the end.

Big pharmas approach to risk - in a high risk business such as drug discovery - is similar to someone with their head stuck in the sand. If big pharma does not change their attitude soon, even their legions of ivy league trained scientist' will not be able to save them from the impending doom.

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16. Dennis on December 6, 2011 10:22 PM writes...

I just love it when the laboratory boys get all worked up over some contrivance they have created to tinker in the incredibly complex chemistry of a living human being and then "release it" to the "oncologists" who are so used to poisoning their patients to death that anything that doesn't kill them outright is considered "therapeutic"! Yes, we now know 6 years down the line, that the "side effects" of these drugs are killing people out here in the real world or, perhaps worse yet, making them wish they were dead.....
Of course this only makes sense as long as you believe the brainwashing that there is "nothing else" out there for cancer that is effective!

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