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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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June 23, 2008

Auroral Activity

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Posted by Derek

If you go to the med-chem or pharmacology literature databases and type "Aurora kinase", you'd better stand back. A geyser of publications will come spraying out, most of them having to do with Aurora A and/or Aurora B as possible targets for cancer therapy. These enzymes are involved in different phases of cell division, among other things, and a lot of evidence points to them as key players in several cancer lines. There are a number of inhibitors compounds known for them as well, in various stages of development, some of which are selective and some of which hit both to different degrees. Attempts to unravel all the functions of the kinases through these compounds, and through various loss/gain of function mutations in cells, have been. . .well, "complex" is a judicious term to use. The functions of the two enzymes may well be tied to each other, so getting a clear look has been hard.

There's a new paper that illustrates just why it hasn't been easy. This one looks at an AstraZeneca compound, ZM447439, which inhibits both Aurora A and Aurora B in enzyme assays, but in cells seems to be the closest match to a clear knockout of B. The authors started with a well-known cancer cell line (HCT-116), and picked out mutants that had acquired resistance to the drug. They turned out, indeed, to have mutated forms of Aurora B in them, and when they introduced those mutant forms into other cells, they also became able to grow in the presence of ZM447439. That's about as good a test of mechanism as you're going to get in the oncology field, and as the commentary on the paper says, "Even had the authors stopped at this point, it would have been an important contribution."

But they kept on digging, and good for them - perhaps they were (rightly) suspicious that everything was working out a bit too neatly. They then chose two other Aurora inhibitors, VX-680 (which hits both forms) and MLN8054, which is known to be selective for Aurora A. When the cells with mutant forms of Aurora B were exposed to the VX compound, they grew anyway - which makes sense from the Aurora B side of things, since they could well have mutated the efficacy away from this compound, in the same way they got away from the AstraZeneca one. But VX-680 definitely seems to hit Aurora A, too - so is that pathway not doing anything at all for efficacy?

Well, when they treated the Aurora B mutant lines with the Aurora-A-selective MLNM compound, they died off, implying that Aurora A inhibition can do the job all by itself, so there's a pretty blatant contradiction here. The authors advance the two hypotheses that have to be looked at: either Aurora A is a good target and the VX compound isn't doing as much against it as everyone thought, or Aurora A inhibition is largely useless (at least in HCT-116 cells!), and the MLNM compound has another target that no one's realized yet. (It's important to realize that this situation could vary from tumor to tumor - here's a suggestion that Aurora A might be the way to go for pancreatic cancer, for example).

And there's another, rather troubling take-home lesson, having to do with the alacrity with which these cells mutated away from sensitivity to the Aurora inhibitors. As the authors put it:

"The rather surprising picture emerging from our studies and from previous studies on Abl and other tyrosine kinases is that the kinase scaffold is very tolerant of mutations in the hinge loop that lines the ATP-binding site. A discouraging consequence of this fact is that these mutations are likely to affect a wide range of ATP-competitive inhibitors—even ones from distinct chemical classes—as most ATP competitors are sensitive to the active site's architecture, to which the mutated residues contribute considerably."

Put simply, the kinases we're targeting have more room to maneuver than we do as medicinal chemists. They can mutate quite a bit and still function, shedding the key binding motifs that our drugs are targeting along the way. We're going to have to work a lot harder to come up with effective combinations.

Comments (12) + TrackBacks (0) | Category: Cancer


COMMENTS

1. Petros on June 23, 2008 8:47 AM writes...

Interesting observatiosn and perturbing for those working on these targets (lots of patents but few currently in the clinic)

It's where seeing the kinase inhibit spectrum of the compounds profiled could be fascinating. In fact the recent Ambit paper included MLN-8054 and this is as potent against DRAK2 as Aurora A. VX-680 doesn't hit that kinase although it hits many more than MLN-8054

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2. DLIB on June 23, 2008 10:23 AM writes...

Stop optimizing by minimizing entropy loss!

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3. RTW on June 23, 2008 10:32 PM writes...

How about irreversible EGFr Inhibitors like CI-1033 or PD 299804? These bind covalently to the APT binding site and allas I think would lessen the likelyhood of a cell surviving and managing to mutate the APT site against the inhibitor. In Kinases inhibition particularly in the ATP site, seldom are they selective, for one kinase.

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4. milkshake on June 24, 2008 1:36 AM writes...

" In kinases inhibition particularly in the ATP site, seldom are they selective, for one kinase."

This rather tiresome fallacy has been repeated since the start of kinase-related medchem projects. In fact you can make nearly perfectly selective kinase ligands - it just turns out that they are not that useful in cancer (the genetic instability/high mutation rate and ability of cancer cells to use alternate paths in cell signalling etc).

We developed one series of compound with a great selectivity for c-Met, unfortunately it did not work on a common mutant varian of c-Met so the company ended up advancing another series, with a more permissive, classical binding mode.

In cancer you can get away with compounds that are outright cytotoxic - the oncologist are comfortable working with drugs that have very narrow safety margin and organ toxicities. And the patients are going to take these meds only for a limited period of time. So the more promiscuous binding mode, scattershot profile and worrisome organ accumulation, the better chance you have developing something efficacious - and chances are that you may not quite understand the excact way your compounds works.

Obviously you cannot use the same philosophy when for example developing drugs to treat inflammation or diabetes.

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5. Petros on June 24, 2008 2:06 AM writes...

Milkshake's comments tend to confirm my outsider's perspective. Sorafenib, sunitinib and imatinib are all pretty non-selective and yet clearly effective (and approved)

Lapatinib is the most selective kinase inhibitor that has got to market, only hitting EGFR, ErbB2 and ErbB4 yet uptake seems to have been slow.

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6. Aspirin on June 24, 2008 11:40 AM writes...

It depends on which kinase you are targeting. In one of the projects I was involved in, we could get selective ligands for an important kinase that did turn out to be useful in treating cancer.

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7. Stephen on June 24, 2008 2:33 PM writes...

Glad to see our paper is attracting positive interest. Re interpreting the VX-680 vs MLN8054 data, may I urge a word of caution here. The key issue is to what extent is Aurora A inhibited in any given experiment. While 200 nM VX-680 sufficiently inhibits Aurora B in DLD-1 cells (Fig. 6B), you need ~800 nM for potent Aurora A inhibition. However, 1-2uM 8054 is probably sufficient for potent Aurora A inhibition in HCT116 cells (Fig. 6E). Hence the caveat "We suspect that this is because the extent of Aurora A inhibition at 200 nM VX-680 is not sufficient to cause cell death, whereas at 1 mM, MLN8054 does inhibit Aurora A enough to suppress viability." We are now trying to test this directly by monitoring cellular Aurora A activity in response to these drugs. Maybe this will be the next installment of our story.

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8. RTW on June 24, 2008 9:42 PM writes...

Well Milkshake - I have been involved in many Kinase projects over a span of 15+ years. Some for cancer some for CV, and some for CNS. I also continue to read as much literature as I can on the subject even now two years removed from the industry. I specifically look at selectivity indications in the papers submitted to journals.

Note also that I never said that selective inhibitors couldn't be discovered. A great example is MEK. There are very selective highly potent compounds that inhibit this but they do not bind in the ATP active site. I am sure there are many other kinase inhibitors that fit this model/mode of action.

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9. srp on June 26, 2008 4:45 AM writes...

I have an ignorant question: Is there some law against throwing a bunch of different but related inhibitors at a tumor, all of which are supposed to hit the same target? So that if the binding site flexes or mutates in some way you're likely to gum it up anyway with some of the members of your brew? All these attempts at targeted elegance make me nervous.

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10. cjh on June 26, 2008 10:21 AM writes...

I tend to agree with srp. The old lesson (remember Wellcome's Septrin, a combination antibacterial) is still valid - hit the pathway at multiple points. Not only are there multiple heterologous kinases of relevance to driving a particular tumour, but the mutants, as homologous targets, should be considered as mulitple targets of the pathway as well. Maybe for some kinases, even their different conformational states might be considered as separate targets. Poses a nice challenge for the medchemists though!

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11. SS on July 3, 2008 3:28 AM writes...

I read somewhere about a change-over from Aurora-A to Aurora-B at higher inhibitor concentrations.

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12. Fig on July 6, 2008 3:41 PM writes...

My bet: the MLNM compound is hitting something else

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