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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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February 21, 2014

Ces3 (Ces1) Inhibition As a Drug Target

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Posted by Derek

Update: the nomenclature of these enzymes is messy - see the comments.

Here's another activity-based proteomics result that I've been meaning to link to - in this one, the Cravatt group strengthens the case for carboxylesterase 3 as a potential target for metabolic disease. From what I can see, that enzyme was first identified back in about 2004, one of who-knows-how-many others that have similar mechanisms and can hydrolyze who-knows-how-many esters and ester-like substrates. Picking your way through all those things from first principles would be a nightmare - thus the activity-based approach, where you look for interesting phenotypes and work backwards.

In this case, they were measuring adipocyte behavior, specifically differentiation and lipid accumulation. A preliminary screen suggested that there were a lot of serine hydrolase enzymes active in these cells, and a screen with around 150 structurally diverse carbamates gave several showing phenotypic changes. The next step in the process is to figure out what particular enzymes are responsible, which can be done by fluorescence labeling (since the carbamates are making covalent bonds in the enzyme active sites. They found my old friend hormone-sensitive lipase, as well they should, but there was another enzyme that wasn't so easy to identify.
One particular carbamate, the unlovely but useful WWL113, was reasonably selective for the enzyme of interest, which turned out to be the abovementioned carboxyesterase 3 (Ces3). The urea analog (which should be inactive) did indeed show no cellular readouts, and the carbamate itself was checked for other activities (such as whether it was a PPAR ligand). These established a strong connection between the inhibitor, the enzyme, and the phenotypic effects.

With that in hand, they went on to find a nicer-looking compound with even better selectivity, WWL229. (I have to say, going back to my radio-geek days in the 1970s and early 1980s, that I can't see the letters "WWL" without hearing Dixieland jazz, but that's probably not the effect the authors are looking for). Using an alkyne derivative of this compound as a probe, it appeared to label only the esterase of interest across the entire adipocyte proteome. Interestingly, though, it appears that WWL13 was more active in vivo (perhaps due to pharmacokinetic reasons?)
And those in vivo studies in mice showed that Ces3 inhibition had a number of beneficial effects on tissue and blood markers of metabolic syndrome - glucose tolerance, lipid profiles, etc. Histologically, the most striking effect was the clearance of adipose deposits from the liver (a beneficial effect indeed, and one that a number of drug companies are interested in). This recapitulates genetic modification studies in rodents targeting this enzyme, and shows that pharmacological inhibition could do the job. And while I'm willing to bet that the authors would rather have discovered a completely new enzyme target, this is solid work all by itself.

Comments (16) + TrackBacks (0) | Category: Biological News | Chemical Biology | Diabetes and Obesity


1. Hap on February 21, 2014 2:26 PM writes...

I am a little surprised that the nitrophenyl carbamate is selective, though the Cravatt group has shown that lots of things are selective that one might not think.

I would assume that there's not all that much around, but is the 4-nitrophenol a redox cycler?

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2. road on February 21, 2014 3:37 PM writes...

FYI - The second link to the 2004 paper is actually a description of *human* Ces3, which is not the orthologue of the *mouse* Ces3 enzyme described here. The nomenclature of carboxylesterases is confusing and, in fact, the human orthologue of *mouse* Ces3 is human Ces1 a.k.a. triglyceride hydrolase (TGH). An appropriate early reference for this enzyme would be something like this:

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3. milfshake on February 21, 2014 4:41 PM writes...

this is a neat approach to pull out targets from a phenotypic screen.

i am wondering why they don't get more of a ppar gamma like effect in fat from this though? i would have expected fatter mice with improved insulin sensitivity. guess maybe it is important in liver or elsewhere....

why is HSL your old friend?

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4. Anon on February 21, 2014 4:58 PM writes...

Exercise and self control are the best drugs for "metabolic disease".

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5. Jon on February 21, 2014 8:51 PM writes...

A para-Nitrophenyl carbamate is relatively reactive; highly likely to label endogenous amines even if apparently selective in certain conditions, one would think. I do worry why so many compounds from phenotypic screening have some reactivity potential. Will we find in years to come that such compounds give readouts by subverting cellular behaviour to something that is not biologically relevant? I guess we don't know, but it would be to be a risk.

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6. JSR on February 21, 2014 10:18 PM writes...

Derek should retitle this entry: as mentioned before, CES3 is the mouse enzyme (and therefore not a drug target). The human version is CES1. It is the 10th most abundant protein in human liver (J. Proteome Res 2010 v. 9 p.50).

It hydrolyzes all sorts of xenobiotics, and activates the ritalin prodrug (among others). There are already known CES1 SNP-carrying people, and some of those SNPs are catalytically inactive (inactive enough to show effects on ritalin PK). A good recent reference: JPET March 2013 vol. 344 no. 3 665-672.

No info yet on metabolic impact of the SNPs--are those folks thin, etc?

The paper is interesting--but is CES1 really a plausible drug target?

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7. John RItter on February 22, 2014 12:12 AM writes...

@4: I don't see how a chemist could possibly believe in free will, which would necessarily have to be a thing in order for "self control" to be a useful concept.

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8. Cellbio on February 22, 2014 12:56 PM writes...

Two ways to limit temptation, self control and stimulus control. Those with self control over emphasize this strategy as a means of limiting intake, but most people do much better with stimulus control. Easier to not eat Oreos when they are not in the cabinet than to avoid the temptation.

Interestingly, exercise is not a great weight loss strategy for most people. Sure, being mostly sedentary is not good, and hammering away for 5K burns will work, but most people respond to burning calories by eating more.

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9. David Young MD on February 22, 2014 11:09 PM writes...

Old Friend? You did notice that he was an author on the article that he linked to. Perhaps Derek was simply saying that he once studied the enzyme.

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10. milkshake on February 23, 2014 3:08 AM writes...

Comment #3 is not from me.

I don't like activated esters in HTS. I don't like mitochondrial decouplers in obesity research. (There are even nuts who are ingesting p-nitrophenol because it makes you slim really, really fast...)

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11. anon the II on February 23, 2014 10:18 AM writes...

I agree with Jon and the real milkshake. When I see a hit compound like WWL229, with an activated ester, I tend to ignore it, try to forget it, and discount future work from the authors.

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12. Pennpenn on February 23, 2014 6:29 PM writes...

@4: Because that's "always" an option and "always" works. Even if I wasn't being sarcastic, I'd still think the work has merit.

@10 Milkshake: I take it they're nuts because it has a high probability of making you really, really dead?

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13. a. nonymaus on February 24, 2014 10:19 AM writes...

Re: 12
Not always dead, there are other stops on the way like hyperthermia-induced cataracts that I've heard of from uncoupling. The archetypal compound in the class is 2,4-dinitrophenol, which used to be prescribed for weight loss until the high rate of side effects was noted.

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14. metaphysician on February 25, 2014 5:31 PM writes...

Silly question, but is there a reason nitrophenols cannot be used for weight loss in a carefully controlled in-patient environment?

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