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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Is GSK Up to Something Else, Too? | Main | Who to Manufacture an API? »

March 13, 2013

Getting Down to Protein-Protein Compounds

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Posted by Derek

Late last year I wrote about a paper that suggested that some "stapled peptides" might not work as well as advertised. I've been meaning to link to this C&E News article on the whole controversy - it's a fine overview of the area.

And that also gives me a chance to mention this review in Nature Chemistry (free full access). It's an excellent look at the entire topic of going after alpha-helix protein-protein interactions with small molecules. Articles like this really give you an appreciation for a good literature review - this information is scattered across the literature, and the authors here (from Leeds) have really done everyone interested in this topic a favor by collecting all of it and putting it into context.

As they say, you really have two choices if you're going after this sort of protein-protein interaction (well, three, if you count chucking the whole business and going to truck-driving school, but that option is not specific to this field). You can make something that's helical itself, so as to present the side chains in what you hope will be the correct orientation, or you can go after some completely different structure that just happens to arrange these groups into the right spots (but has no helical architecture itself).

Neither of these is going to lead to attractive molecules. The authors address this problem near the end of the paper, saying that we may be facing a choice here: make potent inhibitors of protein-protein interactions, or stay within Lipinski-guideline property space. Doing both at the same time just may not be possible. On the evidence so far, I think they're right. How we're going to get such things into cells, though, is a real problem (note this entry last fall on macrocyclic compounds, where the same concern naturally comes up). Since we don't seem to know much about why some compounds make it into cells and some don't, perhaps the way forward (for now) is to find a platform where as many big PPI candidates as possible can be evaluated quickly for activity (both in the relevant protein assay and then in cells). If we can't be smart enough, or not yet, maybe we can go after the problem with brute force.

With enough examples of success, we might be able to get a handle on what's happening. This means, though, that we'll have to generate a lot of complex structures quickly and in great variety, and if that's not a synthetic organic chemistry problem, I'd like to know what is. This is another example of a theme I come back to - that there are many issues in drug discovery that can only be answered by cutting-edge organic chemistry. We should be attacking these and making a case for how valuable the chemical component is, rather than letting ourselves be pigeonholed as a bunch of folks who run Suzuki couplings all day long and who might as well be outsourced to Fiji.

Comments (10) + TrackBacks (0) | Category: Drug Assays | Drug Development | Pharmacokinetics


COMMENTS

1. Anonymous on March 13, 2013 8:58 AM writes...

Why not run both exercises in parallel. Make a lot of complex structures and explore their protein targets. Make a lot of complex structures and explore how they get into cells. Is it transporter mediated (and how does disease state affect this - see Ciarimboli PloS 2012), what's the SAR - or at least what areas of complex chemistry space get into cells.

Nice project for an academic drug discovery lab - anyone doing it ?

Permalink to Comment

2. marcello on March 13, 2013 9:36 AM writes...

Molecules from University of Michigan disrupting p53/MDM2 interaction as well as Roche's nutlins are a success story combining drug-likeness (maybe not brain penetrating, but oral) and complex structure indeed mimicking helical display of peptide motif

Permalink to Comment

3. weirdo on March 13, 2013 10:21 AM writes...

Nature Chemistry is asking me for money for that review . . . bummer.

Permalink to Comment

4. Curious Wavefunction on March 13, 2013 10:25 AM writes...

As I mentioned in my take on stapled peptides, they are a tool, just like any other tool in drug discovery. To declare them as a panacea and to consign them to the ashes are both extreme reactions.

Permalink to Comment

5. truckerchemist on March 13, 2013 10:26 AM writes...

Too funny, the lack of chemistry jobs forced me to do just that, resort to trucking. I am able to make 6 figures with a specialized form of trucking in the oilfield. The money is being used as seed capital for a chemistry based business. What we have to do to survive these days.

Permalink to Comment

6. Chemjobber on March 13, 2013 10:39 AM writes...

@5: Truckerchemist: I beg you, e-mail me at chemjobber -at- gmaildotcom. I would love to hear your story. Confidentiality guaranteed.

Permalink to Comment

7. baseball fan on March 13, 2013 11:10 AM writes...

I agree with marcello (#2) the Wang group at the University of Michigan has made spectacular progess on multiple protein-protein interaction targets.
The fact that there are currently at least 5 inhibitors of the MDM2-p53 protein-protein interaction in phase I trials, is testament that Derek's prognosis on this field may be a little too dark. (Roche x2, Merck, Sanofi, Novartis)

While it may be true that PPI inhibitors will always be on the knife edge of drugability, I strongly believe that it's a tractable problem.
An example of an extremely potent PPI inhibitor that (probably) fits into Lipinski's rules is J Med Chem 2012, 55, 4936 where the group used sophisticated structure-based design to optimize the shape of their molecules.

Permalink to Comment

8. Stu on March 13, 2013 11:10 AM writes...

@weirdo - the Review article should be free to those who are registered on nature.com, but it looks like it isn't at the moment (someone correct me if I'm wrong). I'm getting someone with the keys to our internet cupboard to try and sort this out...

Permalink to Comment

9. Stu on March 13, 2013 11:23 AM writes...

@weirdo - should be fixed now, Review should be free to nature.com registrants...

Permalink to Comment

10. WB on March 14, 2013 8:36 PM writes...

Maybe you can get lucky with macrocycles as well. They are rigid enough to bind well, and just might disrupt the protein-protein interaction.

Permalink to Comment

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