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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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April 5, 2007

Awful, No Doubt. But Not As Awful as Before?

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Posted by Derek

Cancer drugs have a terrible history in clinical trials. The most definitive figure, from development candidates of the 1980s and up to the mid-1990s or so, was a cold, hard, 95% failure rate. That beat even the central nervous system (CNS) drug category, which is a spacious haunted mansion all its own. One reason for this is that all kinds of things get thrown at oncology targets, because there's so much unmet need in the category. Whenever someone comes up with a new technology - monoclonal antibodies, antisense DNA (or RNA interference), disease-altering vaccines, etc. - you can bet that someone's going to try it out on a cancer target. Not all this stuff is going to work, needless to say.

But I wonder if that figure still holds. Starting later on in the 1990s, and gathering speed ever since, a lot of the small-molecule drug candidates in the cancer area have been kinase inhibitors. Now, back when I took my first pharma job, those compounds weren't in very good favor, partly because the key structural motifs that everyone uses today hadn't been worked out yet. If you mentioned kinase inhibitors in the labs, likely as not someone would spit in the sink and say something rude about staurosporine.

That was one of the early potent kinase inhibitors, a fairly nasty natural product. (Note: outdated web page in that link, which fits the subject). All sorts of people worked on staurosporine-like compounds during the 1980s and beyond, and most all those projects came to grief of one sort or another. It gave the whole field an unhealthy look.

There were also good reasons to think that no really selective kinase inhibitors could be discovered (since the enzymes have many structural similarities), and that the resulting broad-spectrum compounds would have just too many side effects to be useful. But molecular biology was uncovering a role for many kinase enzymes in cancer and other disease states, so people kept taking a crack at the area, and finally some far less ugly compound classes were discovered that broke the field open. Once decent compounds were in hand, it was found that they weren't as toxic as everyone had feared. Selectivity was still an issue, but you could sort of tune the structures to inhibit various groups of kinases over others.

I would not want to hazard a guess as to how many kinase inhibitors have gone into development over the past ten or twelve years. It's a pile, for sure - just look at KinasePro and Xcovery to get the idea. I will guess, though, that they haven't failed at quite that horrific 95% rate, and that a 1995-2010 survey of the field will show an improvement. Mind you, the record-holder in the earlier survey was, cardiovascular area, where only about 85% of the compounds collapsed, so don't think I'm talking about a huge increase. But when only one out of twenty of your drugs makes it, getting up to two in twenty means that you have twice as many drugs.

Comments (11) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History


COMMENTS

1. Wavefunction on April 5, 2007 4:51 PM writes...

I think that the conventional thinking about kinase inhibitors well demonstrates the pitfalls of assumptions. It was easy to think that because all kinase inhibitors are blocking the ATP binding site, they must be non-selective. However, recent work has shown that, not suprisingly, there are subtle but important differences in these active sites that nature has fine-tuned. It's only now that we can think of exploiting these differences (like subtle differences in Van der Waals interactions). The other fact which is becoming clear is that there are two other ways of targeting kinases; blocking the substrate binding site, which is part of the general trend of targeting protein-protein interactions, and targeting some allosteric site. Again, all this is easy to say but much more difficult to reduce to practice, but the point is that the evolution in trends concerning thinking about kinase inhibitors demonstrates again that things are more possible than one thinks. There's always some cause for optimism.

Permalink to Comment

2. Chrispy on April 5, 2007 6:38 PM writes...


Are there selective kinase inhibitors? Gleevec sure isn't. The kinase inhibitors make the SSRIs look, um, selective. (This isn't to say that the compounds don't have efficacy, just that the target-based dogma is crumbling a bit.)

Permalink to Comment

3. KinasePro on April 5, 2007 7:05 PM writes...

Thanks for the nod Derek.

On selectivity - SGX-523 claims to be >1000 fold selective for c-Met vs. other kinases, and there are plenty of others turning up. It certainly can be done. A scant amount of googling will turn up a nice pdf on the SGX stuff (w/o structures).

Staurosporine analogs aren't dead though. Cephalon has one in the clinic, enzastaurin was very recently granted orphan status, and it seems ruboxistaurin is perennially on the doorstep to approval.

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4. milkshake on April 6, 2007 12:23 AM writes...

The thing is that highly selective inhibitors are not allways best in cancer and a rather dirty drug can be tolerated if it significantly prolongs the survival. The patient dies or goes to long-term remisiion - in either case he will take the drug for maybe half a year or so.
You want clean inhibitors in other therapeutic areas - diabetes, inflammation, neurodegenration, cardiovascular etc.

Permalink to Comment

5. Curcumin on April 6, 2007 9:58 AM writes...

The thing is that highly selective inhibitors are not allways best in cancer and a rather dirty drug can be tolerated if it significantly prolongs the survival

I am not so sure about that...dirty drugs with toxic profiles are not going to have good patient compliance, and the probability that people will stop taking them will be relatively high, thus offsetting the long survival benefit.

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6. Chrispy on April 6, 2007 3:09 PM writes...


KinasePro --

You're certainly the expert, but I, for one, would not believe any company propaganda (especially from SGX). The thing is that there are just SO MANY kinases. Heck, I work for a company which claims to have a highly selective kinase inhibitor, and I don't even believe them!

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7. Hap on April 6, 2007 3:25 PM writes...

Chrispy-

It's sort of off-topic, but wouldn't the lack of trustworthiness/believability seem to be a problem if true for pharmaceutical companies in general? People with less technical experience might be more inclined to believe companies when they say they have something, and be more unhappy with those companies when it turns out that the companies don't really have what they say they do. False hope tends to hurt more sometimes than no hope at all.

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8. KinasePro on April 7, 2007 12:29 PM writes...

Expert? More likely just an unnaturally preoccupied observer! While a lot can be said about selectivity, ultimately efficacy and side effects are all that matter.

On SGX - they have so few programs (ABL/Met/Jak2) that fibbing about one of the unpartnerred two would be suicide. They released an image of 523 + c-Met xray and the a-loop appears to indicate an unusual DFG conformation >> I'm a believer!

I agree with Milkshake, and think the 20 million $ question is: Will a selective compound like this be as efficacious and better tolerated then a compound like XL-880 (a phase ii c-met inhibitor which inhibits VEGF and a number of other kinases)

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9. Eric Johnson on April 8, 2007 3:36 PM writes...

The surprise over the finding that kinases are in fact more or less selectively targetable, was impressed on me in class.

I also had my attention grabbed by R207910, a potent anti-mycobacterial which apparantly targets no less conserved a molecule than the F0F1 ATP synthase (Science 2005, PMID 15591164). Strikingly, this agent has proven nearly inactive even on bacteria outside Mycobacterium, so it's not shocking that it also didn't overtly harm tubercular mice during efficacy experiments.

Is there any general lesson to be drawn from these examples? Are homologous proteins going to turn out to be more selectively targetable than people generally thought? Not being immersed in med chem or protein homologue diversity, I myself can't do anything more than just point at these examples, not really knowing how common or extraordinary they may be.

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10. Retired Med. Chemist on April 8, 2007 7:37 PM writes...

In the case of c-Met, both 'selective' and less selective inhibitors (cross inhibit VEGF etc.) have been reported. The clinical advantage of one over the other has yet to be demonstrated. In certain tumors, mutations in the c-Met receptor
are believed to be oncogenic---thus, making it
a more reliable target.
The success of other RTKI's like Tarceva, Sutent,... seems to indicate this may be a very fruitful approach.

Permalink to Comment

11. milkshake on April 8, 2007 7:45 PM writes...

We had two classes of c-Met inhibitors at Sugen, one of them was pretty resistant to oncogenic mutations and the other one was not. It depends on the binding mode.

The common wisdom "All kinases have the same ATP binding site that is highly conserved and therefore is hard to get a selective inhibitor" was completely wrong. It turns out that ATP is a lousy binder with Ki in high millimolar range. If ATP or ADP were tight kinase bindes there would be no turnover. It also turns out that most kinase ATP binding sites are quite larger than what is required for ATP and there are significant differences.

Sometimes you have closely-related kinases with very similar binding sites so it is hard to get a good selectivity with a particular class of inhibitors - but switching to another scaffold with different binding mode can solve the selectivity problem

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