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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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July 15, 2008

Metabolic Hope Springs Eternal

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Posted by Derek

Now, if I were still doing metabolic disease work, I'd be all over this target: CAMKK2, which is mercifully short for "Ca2+/calmodulin-dependent protein kinase kinase 2". (Kinase nomenclature has been out of hand for years, in case you're wondering).

CAMKK2 is right in the middle of a lot of pathways that are known to be important for regulation of appetite and glucose levels, namely ghrelin, AMPK, and NPY. These have been rather hard to approach directly with small molecules, or (in the case of NPY) hitting them hasn't been enough by itself. That's the problem with a lot of potential therapies for obesity, as I've mentioned here before. As a behavior, eating is full of overlapping backup redundant pathways, since we're all descendants of creatures that ate whatever they could, whenever they could. The ones whose feeding could be easily shut down or interrupted didn't make it this far.

So even though the field is littered with things that haven't worked out, perhaps a target like this, which seems to be more upstream, might have a better chance of success. We're definitely going to find out. Given the number of companies interested in this area, and the number with kinase expertise, someone's going to be able to take a good swing at this one. The benefits might go beyond weight loss - animals given a known inhibitor (STO-609, a Sumitomo compound) were also resistant to the bad effects of a high-fat diet, putting on less weight than controls and showing better glucose control.

Of course, the fact that Sumitomo had a compound years ago that hits this target so well makes you wonder what ever happened to it. I can't find much about why it didn't progress, but you can be sure that other people are asking that same question right now. . .Update: see this comment for more on this topic. . .

Comments (11) + TrackBacks (0) | Category: Diabetes and Obesity


COMMENTS

1. FormerMolecModeler on July 15, 2008 9:55 AM writes...

So you want to develop a kinase drug for a chronic indication for a target that's in the brain? So not only does this kinase inhibitor have to be selective, but it has to pass the blood-brain barrier as well.

Sumitomo claims it's selective, but against how many other kinases did they test it? (I haven't read the paper)

Good luck with this one. Man have I gotten cynical.

Permalink to Comment

2. Petros on July 15, 2008 10:22 AM writes...

In assessing kinase inhibitors in development last year I talked to a number of experts in the field. Their consensus was that all kianse inhibitors for chronic conditions need to be very selective, hence the lack of success with p38 inhibitors.

On STO-609

Philip Cohen's group reported last year

"STO 609 has been identified as an inhibitor of CaMKKα and CaMKKβ, which are ‘upstream’ activators of CaMK 1 and 4. CaMKKβ also activates AMPK in neuronal cells [83] and T-cells [84]. When tested against our extended panel, CaMKKβ was inhibited about 10-fold more potently than CaMKKα. However, STO 609 was also inhibited ERK8, MNK1, CK2, AMPK, PIM2, PIM3, DYRK2, DYRK3 and HIPK2 with similar potency to CaMKKα (Tables 5 and 7). STO 609 suppresses CaMKK activity almost completely when added to cells at 25 μM (D. G. Hardie, personal communication). However, although this compound has been used to implicate CaMKKs in the activation of AMPK, the present study indicates that STO 609 is not a specific inhibitor and results obtained by using it should be interpreted with caution."

Permalink to Comment

3. FormerMolecModeler on July 15, 2008 10:58 AM writes...

Totally agree Petros. They don't say how big their "extended panel" is, but typically pharma companies would run maybe 30-50 on a monthly basis if they have active kinase chemistry going on. An Ambit screen would be most instructive, but I don't think this compound has a way forward.

To be really selective, the molecule will likely have to be fairly large, and while that may not be an issue for non-CNS targets, I suspect it would be problematic for getting into the old branium.

Permalink to Comment

4. anonymous on July 15, 2008 1:12 PM writes...

I'm sorry but I've seen this movie one too many times (leptin, melanocortins, orexin, NPY, cannabinoids, etc). One thing that should not be surprising but is a hallmark of obesity papers is to show that not only does your knockout or compound decrease food intake and weight gain on a high fat diet but it also improves glucose clearance. Guess what, it better. The obesity is what leads to the glucose intolerance! What you really want to see is similar food intake but reduced weight gain and in this paper there was reduced food intake with the antagonist. That's probably a bad sign. Look at that CNS expression and tell me that there aren't going to be any behavioral consequences to this target. I'm thinking of rimonabant right now. As far as a logical target it may be as good as any but...

I do believe there is something to regulating food intake through the CNS (in particular hypothalamus) but I'm not much of an optimist. As has been pointed out many times before in this blog, the CNS is a house of cards and you're usually removing one of the bottom ones!

Permalink to Comment

5. Cellbio on July 15, 2008 2:17 PM writes...

Quick add on to Petros' comments:

Highly selective p38 inhibitors are very possible. Have seen one that hit p38 alpha and beta, subnanomolar, and no ther kinase in the full Ambit panel. Still didn't make it out of safety studies for chronic indication. Any one got an indication for acute use?

Permalink to Comment

6. leigh on July 15, 2008 2:40 PM writes...

my concern is that the more upstream you go in a pathway, the more likely you are to see undesired effects. especially with molecules like kinases- how many other systems will be perturbed by inhibiting this protein? what gain or loss do you have in response to that? a brief search found a role for downstream CAMKIV in hippocampal activation of CREB- in my opinion, that's not an ideal place to go playing around.

i appreciate the optimism but i would be feeling cautious here.

Permalink to Comment

7. joe on July 15, 2008 4:11 PM writes...

Derek,
I like the way you put up the blog about the kinase, nice way to get some info. on the target

Permalink to Comment

8. milkshake on July 15, 2008 6:50 PM writes...

I think the topical use for psoriasis (and many other scenarios of skin inflammation) is a real posibility, with p38 compounds. Especially if you make them greasy but metabolically unstable (to limit the systemic exposure).

Permalink to Comment

9. Petros on July 16, 2008 2:17 AM writes...

On the p38 inhibitors I'm not surprised that there are highly selectiev compound but I'm unaware of any scientific publications describing such.
My comment on these related to the near 20 years that this target has been pursued, with compounds identifeid at SB (CSAIDs) before theyr identified the target. Since then a lot have gone down either preclinically or clinically but, aside from the first Vertex compound (CNS tox), little has been published on the reasons for failing although haptotoxiicty is usually bandied around as the primary cause. (BTW BI's lead compound made it to PIII for psoriasis before dying)

Permalink to Comment

10. from_sgc on July 16, 2008 4:10 AM writes...

We run STO-609 through 33 kinases and it hit 6 with the similar potency as CaMKK2.

Permalink to Comment

11. Anonymous on July 18, 2008 10:39 PM writes...

Petros take a look at ARRY's p38 inhibitor.

Permalink to Comment

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