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Derek Lowe The 2002 Model

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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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« DNA Can Be Messed With More Than You'd Think | Main | Ben Cravatt At The Challenges In Chemical Biology Conference »

July 25, 2013

Kurt Deshayes At The Challenges in Chemical Biology Conference

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Posted by Derek

Kurt Deshayes of Genentech has been speaking at the Challenges in Chemical Biology meeting, on protein-protein inhibitor work. And he's raised a number of issues that I think that we in drug discovery are going to have to deal with. For one thing, given the size of PPI clinical molecules like ABT-199, what does that tell us about what makes an orally available molecule? (And what does that tell us about what we think we know about the subject?) You'd think that many (most?) protein-protein inhibitors will be on the large side, and if you were to be doctrinaire about biophysical properties, you wouldn't go there at all. But it can be done - the question is, how often? And how do you increase your chances of success? I don't think that anyone doubts that more molecules with molecular weights of 1000 will have PK trouble than those with molecular weights of 300. So how do you lengthen the odds?

Another point he emphasized is that Genentech's work on XIAP led them to activities that they never would have guessed up front. The system, he points out, is just too complicated to make useful predictions. You have to go in an perturb it and see what happens (and small molecules are a great way to do that). I'd say that this same principle applies to most everything in biochemistry: get in and mess with the system, and let it tell you what's going on.

Comments (7) + TrackBacks (0) | Category: Chemical Biology


1. Bruce on July 25, 2013 11:35 AM writes...

A high MW compound will have a better chance of getting across a membrane if it can mask its heteroatoms with internal hydrogen bonds. Check out Med. Chem. Commun. 2011, 669-674.

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2. Anonymous on July 25, 2013 1:42 PM writes...

@1: To go a step further, large molecules like macrocycles have been shown to undergo a hydrophobic collapse which allows them to cross membranes quite well. Cyclosporin A is a classic example of this phenomena and may be something that can be designed for with the right structural tools.

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3. samadamsthedog on July 25, 2013 3:22 PM writes...

@2: Could you tell us how this works? Hydrophobic collapse buries hydrophobic groups (hyd's them ? :-) ), whereas to cross a membrane you presumably need them exposed, which is consistent with @1's comments about the need for large molecules to "mask" their heteroatoms in order to cross membranes.

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4. Curious Wavefunction on July 25, 2013 3:29 PM writes...

@2: Cyclosporin actually forms intramolecular hydrogen bonds rather than undergoing a hydrophobic collapse. In fact as #3 indicated, it exposes hydrophobic groups to the membrane while hiding them in water. Cyclosporin also has a fair number of its amides N-methylated to enable membrane permeation.

As someone working in the macrocycle field I am very much interested in the topic of engineering these kinds of interactions into macrocycles to make them more permeable. There is no general recipe yet, although hydrogen bonding, N-methylation and use of non-natural amino acids are all strategies that have worked.

I would recommend taking a look at Matt Jacobson's and Scott Lokey's recent work on macrocycle permeability; both their groups have made some noteworthy advances in this area.

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5. Anonymous on July 25, 2013 3:32 PM writes...

My apologies, I meant 'hydrophilic collapse' and shielding of hydrophilic groups to expose a hydrophobic exterior. Typo.

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6. Anonymous on July 25, 2013 3:38 PM writes...

@4: Interestingly, the earliest paper I have been able to find on this subject is from Navia and Chaturvedi at Vertex.

I agree with you that the concept of engineering this functionality in to macrocycles is very interesting. I am curious to see how it works with cyclic peptides and how it may branch out in to more 'macrolide-like' macrocycles.

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7. weirdo on July 25, 2013 4:44 PM writes...

OK, OK, I'm not at this conference, so I don't know exactly was stated, but, really?

There is no arguing the fact that one has a better chance of a low molecular weight drug being highly orally bioavailable than a high molecular weight drug.

There is also no arguing the fact that many, many drugs that "violate" the rule of 5 have very good oral BA.

There is no conflict here. Again, if one simply reads Chris Lipinski's original paper, there is no issue. It's how those concepts have been brutally (mis)applied that is the problem.

But what does ABT-199 tell us about oral BA?

Um, nothing. (Unless it's a substrate for a not-yet-discovered transporter).

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