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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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January 11, 2004

A New Cancer Target - Maybe

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Posted by Derek

In my industry, you hear a lot of talk about drug targets and their relative chances of success. Targets fall into several broad classes, and when you take a close look, there are clearly some that are easier to hit than others. The G-protein coupled receptors (GPCRs) are one of those (antihistamines and beta-blockers are classic examples), and various hydrolytic enzymes are another (ACE inhibitors, HIV protease inhibitors, PDE inhibitors like Viagra, etc.)

But there are some other categories that are severely under-represented. "Interaction" targets is what I'd call a broad group of these. The ligands for the easier enzymes and GPCRs fit into defined binding pockets, which have evolved for small molecules, It's the old lock-and-key picture. But trying to affect the binding between two proteins, or of a protein with a stretch of DNA/RNA - now, that's something else again. There's no single binding pocket there, at least not on the scale of a drug-sized molecule. Instead of fitting different-shaped keys into existing locks, we're faced with trying to wedge something in between a door and its frame.

It's hard to get in there, and our molecules are often too small to have much effect. But the number of drug targets in this class is huge; we're going to have to come to terms with them eventually. . But for now, one of the best ways is to carefully study the various high-value targets and see if there are some that look more likely to work, given what we already know how to do. That's what a group at Roche has been up to recently, and they've reported their success in an online preprint in Science.

They're after a protein called MDM2, which acts as a brake on the activity of a more famous protein from the p53 tumor-suppression gene. In many cancers, it would be good to block this interaction and get the p53 system as back to being revved-up as possible. (Of course, in many other cancers, this gene has already been taken out of action by one mutation or another, which is probably a key step in their formation. Those won't be candidates for MDM2 blocking therapies.)

In 1996, a group at Sloan-Kettering published an X-ray crystal structure of the two proteins, which showed that there was a fairly clear pocket that seemed responsible for a lot of the binding. It looked like a possible candidate for a small molecule, but this is the first report of real success in targeting it (although others are hard at work.) The Roche group found some polyaryl imidazoline structures through high-throughput screening that seem to do the job. One of them is even orally active in a rodent tumor model, which is quite an accomplishment. And as proof of the mechanism, the compounds are inactive against those cancer cell lines that have already lost their p53 gene.

This is good news, since we can always use another route to cancer therapy. But I'm not sure how broadly applicable this is going to be. I'm sure that there will be talk of new interest in protein-protein drug targets, but this one is (unfortunately) an anomaly. That type of small, reasonably well-defined pocket that plays a role here doesn't show up that often, and it's not like people haven't been looking. News that these things can succeed will stimulate more work in the area, true. But that's where a lot of the effort was going already, because other protein-protein targets have seemed destined to fail.

My mental picture of those targets is of two oil tankers slowly coming together, brought closer as dozens of small grappling hooks whiz out and clang onto different parts of their decks. With a small molecule, we're trying to interfere with that by sticking a fishing boat in between them. Not easy, but we're going to have to figure it out eventually. Protein-protein interactions are a hot topic these days (go off and Google "proteomics", but stand well clear while you do it!) so we're bound to learn a lot more in the next few years.

For now, congratulations to Roche as they move forward toward the clinic. They'll be the first to find out what blocking MDM2 binding is going to do to animals - how well it'll treat those with cancer, and what side effects it might have on those without. I hope there's daylight in between those two groups!

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