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.

This article was originally published with the title Outsmarting Cancer.

4 Comments

1. 1. JamesDavis 08:46 AM 10/14/11

   Have you considered using insulin and liquid mega vitamins. It use to be called, when we came out with it in 1953, "Insulin Shock Therapy", but it was discontinued and placed upon the shelf because, at that time, they didn't know that much about insulin. Inject the liquid vitamins into the body to strengthen it and then use the insulin to make the body inhospitable to the cancer. They have a 90% success cancer kill rate in Mexico using the therapy we developed in 1953.

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2. 2. paulwakfer in reply to JamesDavis 09:11 PM 10/14/11

   The pharma industry is not interested in what "works" against cancer (or any other disease), but rather what chemicals they can patent and show to have sufficient benefit for some disease, that the FDA will approve them, and doctors will subscribe them (at exorbitant prices because of all the effort taken and the effective medical/pharma monopoly).
   
   I am not against the profit motive here or anywhere else. The reason unpatentable methods and products do not get fully tested, promoted and used is because people have not yet learned that their long range best interest is served by not trying to get something for little or nothing, but rather always rewarding the producers of value whether or not those producers have a legal patent or copyright. I have written elsewhere on this fully ethical social trading method which I call "Value for Value".
   
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3. 3. ravinene 01:12 AM 10/15/11

   Is a two step process possible? Step 1: Introduce some chemical that can be used to "break" the flat undruggable protein molecule. Step 2: It might then be possible to attach a small drug protein molecule to attach itself to the "freed" bonds of the flat protein

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4. 4. bucketofsquid in reply to JamesDavis 11:57 AM 10/28/11

   I did a bit of research on cancer death rates in Mexico and the data they have compiled shows a steady increase in cancer and cancer fatalities since 1960. Since 1922 the cancer rate in Mexico has been lower than North America and the EU but it is gradually closing the gap. This is despite some cancers decreasing in frequency and fatality rates.
   
   Since cancer is a large array of many diseases with many different causes this isn't surprising. There is no magic bullet, cure all treatment. Your post is like so many other posts you have made where you make wild claims with no research to back it up. Please stop.

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