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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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« Kurt Deshayes At The Challenges in Chemical Biology Conference | Main | More Behind-the-Scenes Maneuvering. How Wonderful. »

July 25, 2013

Ben Cravatt At The Challenges In Chemical Biology Conference

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Posted by Derek

Ben Cravatt is talking about this work on activity-based protein profiling of serine hydrolase enzymes. That's quite a class to work on - as he says, up to 2% of all the proteins in the body fall into this group, but only half of them have had even the most cursory bit of characterization. Even among the "known" ones, most of their activities are still dark, and only 10% of them have useful pharmacological tools.

He's detailed a compound (PF-3845) that Pfizer found as a screening hit for FAAH, which although it looked benign, turned out to be a covalent inhibitor due to a reactive arylurea. Pfizer, he says, backed off when this mechanism was uncovered - they weren't ready at the time for covalency, but he says that they've loosened up since then. Studying the compound in various tissues, including the brain, showed that it was extremely selective for FAAH.

Another reactive compound, JZL184, is an inhibitor of monoacylglycerol hydrolase (MAGL). Turns out that its carbamate group also reacts with FAAH, but there's a 300-fold window in the potency. The problem is, that's not enough. In mouse models, hitting both enzymes at the same time leads to behavioral problems. Changing the leaving group to a slightly less reactive (and nonaromatic) hexafluoroisopropanol, though, made the compound selective again. I found this quite interesting - most of the time, you'd think that 300x is plenty of room, but apparently not. That doesn't make things any easier, does it?

In response to a question (from me), he says that covalency is what makes this tricky. The half-life of the brain enzymes is some 12 to 14 hours, so by the time the next once-a-day dose comes in, there's still 20 or 30% of the enzyme still shut down, and things get out of hand pretty soon. For a covalent mechanism, he recommends 2000-fold or 5000-fold. On the other hand, he says that when they've had a serine hydrolase-targeted compound, they've never seen it react out of that class (targeting cysteine residues, though, is a very different story). And the covalent mechanism gives you some unique opportunities - for example, deliberate engineering a short half-life, because that might be all you need.

Comments (8) + TrackBacks (0) | Category: Chemical Biology | The Central Nervous System


1. bad wolf on July 25, 2013 4:06 PM writes...

Wow, talking about papers from 2009 and 2008? I thought this was conference was 'current' challenges in Chem bio.

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2. ScientistSailor on July 25, 2013 7:00 PM writes...

Sanofi canned their covalent FAAH inhibitor due to lack of efficacy in the clinic. And it was just as potent/selective as Pfizer's...

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3. Derek Lowe on July 25, 2013 7:30 PM writes...

That was part one of the talk - there was newer stuff as it went on, fear not.

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4. bad wolf on July 25, 2013 9:03 PM writes...

Sorry, missed the 2012 paper. Glad to hear recent stuff is discussed--nothing more deflating than hearing history instead of news.

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5. SAR screener on July 26, 2013 6:24 AM writes...

Presumably with covalent inhibitors you need extremely good selectivity because once a cpd binds and reacts it’s stuck on the enzyme and so things like competition with substrate for your off target enzyme, which may save you in non-covalent systems are no longer effective.

How did they measure the selectivity?

IC50s can be misleading for covalent inhibitors as ultimately, if you leave them for long enough, all covalent inhibitors will have an IC50 of ½ [E].

Ranking by kinact/Ki gives a better idea of selectivity – it’s roughly analogous to using kcat/Km for comparing substrate selectivity, with kinact telling you how fast the compound reacts once it binds and Ki being a measure of affinity.

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6. Mark on July 26, 2013 5:26 PM writes...

I've worked extensively on FAAH inhibitors, and in particular, this same class of arylureas. I've also worked with Cravatts company that does the activity-based profiling. Its a great technique and provides a lot of insight into the potential off-target activity of this class.

Problem with this class of inhibitors is that potency doesn't correlate with efficacy. For all the papers that talk about URB597, there is a host of other drugs that are just as potent, if not moreso, that don't show any efficacy at all.

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7. weirdo on July 26, 2013 6:00 PM writes...

Mark: Re: efficacy & potency.

Why would one expect any relationship between "potency" and efficacy? For covalent inhibitors, as mentioned above, potency and selectivity are simply a matter of time. In addition, enzyme turnover is a feature often overlooked. Is it not possible for some covalent inhibitors to drive the target enzyme into a conformation that is more readily recognized by proteases (or other processing enzymes) and thus result in more rapid synthesis of new target protein? If one does not get the warhead electrophilicity just right, it may never have the chance to get to the target.

Lots of targets are going to great candidates for covalent warheads; those who figure that out early (and address/anticipate the new issues involved) are going to have a distinct advantage.

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8. anonymous on July 26, 2013 6:21 PM writes...

@5 and 7:
When those idiosyncratic anaphylactic events hit you in the arse in the Clinic, we'll see just how popular covalent inhibitors remain> anyone heard of penicillin allergies?

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