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See Inside October 2011

Outsmarting Cancer: Why It's So Tough

A biologist talks about what makes disease-causing proteins so difficult to target with drugs



Courtesy of Brent Stockwell

Name: Brent Stockwell
Title: Associate professor, Columbia University
Early career scientist, Howard Hughes Medical Institute
Location: New York City

There really is a crisis now occurring in the pharmaceutical industry. For the past 10 to 15 years the number of new drugs has been declining because it’s becoming harder and harder to create new medicines.

A lot of people have speculated about why. One ex­planation I support is that we’ve run out of proteins that can be targeted with drugs. The targets that are left are “undruggable.”

Proteins that are considered undruggable don’t have large pockets or cavities inside them and instead are relatively flat on their surfaces. There’s no obvious site for a small molecule, a therapeutic candidate, to interact. Fifteen percent of proteins are considered druggable. What percent of proteins modify disease? It might be somewhere around 10 to 15 percent. There’s no correlation between whether a protein is druggable and whether it’s disease-modifying. Most proteins that drive disease processes are actually undruggable.

The reason I wrote The Quest for the Cure [Columbia University Press, 2011] was that I thought this was an important problem that most people are not aware of—even in science, let alone the general public. And if we can get the best minds to tackle this question, I am optimistic that we will ultimately be successful in finding solutions to most, if not all, of these proteins.

In my lab, our goal is to find proteins that control cell-death mechanisms in cancer and neuro­degenerative diseases and then to find small molecules that can inhibit or activate those proteins.

We’re at a relatively early stage, but we have tried to target one class of proteins called E3 ligases, which are involved in pretty much every disease and cellular process. They have been considered undruggable, however, because there are no small molecules that can block their activity. Our strategy was to model, on a computer, the way a small molecule interacts with a particular E3 ligase and to predict small molecules that might interact favorably. Then we picked the best 2,000 compounds to test experimentally.

Out of that came a very striking, potent inhibitor on which we’ll be publishing a paper in the next few months. We are now using this same strategy on other proteins. I think it’s going to become more and more apparent in the next five to seven years that we really are running out of drug targets. Then, in the 10- to 15-year horizon, some of these new approaches will be successful, and that will lead to some powerful new drugs. It will take some time to get there, though.

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