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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: Twitter: Dereklowe

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July 28, 2010

PPAR: A Veil Is Lifted, At Last

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Posted by Derek

I used to work on compounds targeting the PPAR family (and nuclear receptors in general). I knew nothing about the field when I started, which is the traditional situation a medicinal chemist is in, but I picked it up. And picked it up. . .and picked up still more information, on and on, as it dawned on me that the whole field was quite possibly beyond our ability to deal with in an organized fashion.

Not that people didn't try, famously Glaxo. They cranked up a huge effort to go after these targets with the full toolbox - structure, pharmacology, med-chem, animal models, the lot. Merck and others did the same, but Glaxo's team were out there front and center at every conference, presenting data and mentioning in asides that they had X dozen crystal structures of that receptor, and this-many compounds heading into development, and so on. Very little has emerged out on the money-making end from all this work, by all the companies who've tried it. Avandia (rosiglitazone) and Actos (pioglitazone) are still the only PPAR-targeting drugs on the market, with Avandia in serious trouble, and they were both developed before anyone knew what their target was.

But there's absolutely no doubt that PPAR subtypes are major metabolic players; it's just that we don't quite know how to untangle the huge number of effects they have. Now a paper from one of the longtime leaders in the field, Bruce Spiegelman, might restore some order. And it does so in an unexpected way.

Upstream of all the hideously complex transcriptional effects, subtly modulated by ligand, by cell type, by time of day and who know what else, Spiegelman's groups has found that it's the phosphorylation of PPAR-gamma by the kinase CDK5 that might be the key. That doesn't alter the broad strokes of transcription, but it does alter specific genes that are associated with obesity and the metabolic syndrome. (It's known that the PPARs associate with a host of other protein cofactors, and this phosphorylation probably affects some protein-potein binding surface).

High-fat diets in rodents crank up CDK5 activity, and a whole list of effective PPAR compounds, it turns out, keep the receptor from being phosphorylated by it. Moreover, insulin sensitivity correlates quite well with the degree of phosphorylation. It really does look as if the code has been cracked - we may finally know what the primary PPAR-linked event is that affects type II diabetes. So, forget all those other assays: just measure the amount of serine-273 phosphorylation and you've done what you need to do?

This work has doubtless caused plenty of people in the metabolic disease field to drop whatever they were holding and start thinking things all over again. There are a lot of questions to answer: what happens if you dose a CDK5 inhibitor? In what other tissues does a high-fat diet alter CDK5 activity? Could you get all the insulin-sensitization effects of a glitazone drug without the side effects, by targeting a drug development program differently? Does CDK5 have anything to do with the cardiac side effects that everyone's so worried about with Avandia? And so on. It's a great result, one of those papers where you really come away knowing something crucial that you didn't before.

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity


1. PharmaHeretic on July 28, 2010 12:03 PM writes...

Hmm.. The old meme about high fat diets causing obesity. Isn't that a big red flag for the quality, or lack thereof, of this guys work.

Seriously, can most people gain weight on a high-fat/ low-carb diet? If anything such a diet in humans is known to cause weight loss and ketoacidosis, NOT weight gain or impaired insulin sensitivity.

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2. Done with PPARs on July 28, 2010 12:20 PM writes...

Another detail of the very complicated molecular story of these transcription pathways, but does not necessarily simplify the situation sufficiently to give a preferred targeted drug approach that will result in better safety than the many very potent experiemental PPARs have demonstrated to date.

You are right Derek, disruption of the pathway(s) have some remarkable biological results, which ramains the big problem that has not been resolved---too much involvement in key biological functions with major safety implications. No matter how many nice, colorful crystal structures may be solved to suggest detailed interactions in a binding cleft, this science still does not provide safety in making a drug for human use.

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3. ronathan richardson on July 28, 2010 12:20 PM writes...

Boy, cdk5 is one of the most broadly important kinases in the genome, so inhibiting it could be a disaster. Although most of its importance seems to be in the brain, so maybe the BBB could be a friend here.

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4. In Vivo Veritas on July 28, 2010 12:50 PM writes...

Hey Heretic, while I find your views on high fat diets...... interesting...... I'll note that the paper used the standard DIO mouse diet - Research Diets D12492: 60% kcal from fat, 20% each carb & protein. So not exactly "low carb" in the Atkins sense, but certainly high fat by anyone's estimate. And that fat is lard, and it puts weight in the form of fat on rodents beautifully. I'd suspect that if a human was maintained on it, they would get fat too (taste issues aside).

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5. retread on July 28, 2010 2:44 PM writes...

#3 True in spades ! Have a look at this:

[ Proc. Natl. Acad. Sci. vol. 107 pp. 2884 - 2889 '10 ] Cdk5 is activated by association with its regulators p35 or p39 or their corresponding cleaved carboxy terminal fragments p25 or p29 (resp.). These are not cyclins however.

Known substrates are tau, beta catenin, Nudel, FAK, synapsin1, ErB, retinoblastoma protein and STAT3.

CDK5/p35 is associated with normal neuron development function. However, CDK5/p25 is associated with neuronal cell death. It is toxic when overexpressed in transformed cell lines, or when generated by cleavage of endogneous p35 in neurons. However there is no difference in the kinetics of tau or histone phosphorylation between CDK5/p25 and CDK5/p35

Known roles for cdk5 in the brain are (1) neuronal migration during development of the cortex (2) regulation of cadherin adhesion (3) regulation of actin, neurofilament and tubulin cytoskeletons (4) regulation of dopamine signaling (5) possible phosphorylation of tau (6) synapse formation.

Mess with CDK5 at your own risk !

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6. MLBpitcher_and_MedicinalChemist on July 28, 2010 4:38 PM writes...

A CDK5 inhibitor probably wouldn't get past animal testing if inhibiting it would have broad adverse effects.

But will this research yield a new molecular entity that would be able to compete against generic rosiglitazone and pioglitazone by providing less side effects/better effect than the aforementioned drugs?

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7. Rock on July 28, 2010 8:02 PM writes...

Clearly the PPARs are not directly inhibiting cdk5 as demonstrated in the paper. The inhibition is more specific. Curious how the old fibrates would behave in that assay. Never could understand how they could be effective given their very weak activity for the PPARs.

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8. NHR_GUY on July 28, 2010 8:20 PM writes...

I worked on PPAR's for much of my career and was always befuddled by the black box understanding we had of the biology and pharmacology. One of the confounding factors when trying to understand PPARs was that you were dealing with a critical biological switch involved in energy usage and storage. Nature in her/his infinite wisdom has made these pathways redundantly and so if you shut down one pathway, you open up another compensatory pathways. This makes sense when considering the crucial role PPARs play in metabolism, but makes research tough. Necessarily you would want these mechanisms to be robust and redundant as they are key to living.
BTW, though it wasn't known at the time, the fibrates target PPAR alpha. Though I don't do PPAR's anymore, I would love to go back and test our compounds under this new paradigm.
BTW Derek, saw one of your PPAR papers and wanted to ask you how you managed to get it published w/o having reported screening data on all three sub-types.

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9. Virgil on July 29, 2010 9:29 AM writes...

Another big (and often ignored) spanner in the works of the PPAR field, is the work of Phipps, showing that platelets contain PPARgamma. Yes, platelets, those little things WITHOUT NUCLEI. What on earth a so-called NUCLEAR receptor is doing in a cell without a nucleus, seems to be lost on 99% of those on the field, but it certainly suggests there are non-DNA-binding mechanisms for signaling by this interesting family of proteins.

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10. steriod receptor on July 30, 2010 10:47 AM writes...


Can't speak for other disciplines. I believe that it is 99% of the NR scientific field knows that there's a lot of non-nuclear, non-genomic actvities. The other 1% is in Pharma R&D leadership roles.

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11. Vince on July 30, 2010 4:03 PM writes...

CDK5 is a fun research topic, but beware any direct attempt at practicality.

Comment #5: between CDK5/p25 and CDK5/p35

Agreed. As an aside, in the CNS, the conversion of p35 to it's truncated, neurally active, form via calpain is an area that is exciting on it's own and a more precise variable to perturb.

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12. Scott on August 2, 2010 7:43 AM writes...

Sorry to nitpick. True there are only 2 ppar-gamma agents available. There is also a few PPAR alpha agents available - namely the fibrates, bezafibrate, fenofibrate.

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