The following is an interview with Brent R. Stockwell, author of The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines.
Q: Why are so few new medicines being discovered?
Brent R. Stockwell: This is one of the big questions in drug discovery. Over the last 15 years, the number of new drugs approved each year has been declining. Meanwhile, the pharmaceutical industry, as well as academic and government researchers, has dramatically increased the amount of money spent on drug discovery and development. Yet this large increase in funding is not translating into new medicines. One explanation for this failure is that we are running out of tractable drug targets–drugs usually function by interacting with, i.e. attaching to, specific proteins within the body, which are called “drug targets.” However, only 2% of the proteins found in humans have been targeted to date with drugs. Most of the remaining proteins are considered “undruggable,” meaning it is difficult or perhaps impossible to make drugs that interact with these proteins. If this is true, it suggests that we are running out of drug targets, and therefore running out of drugs. This could be the explanation behind the challenging state of drug discovery, and the paucity of new medicines.
Q: What is it about these undruggable proteins that make them resistant to targeting with drugs?
B.R.S.: Proteins are large molecules with specific three-dimensional shapes. The more tractable proteins have large crevices, or pockets, on their surfaces into which small molecule drugs can snugly fit. When this happens, the drug alters the function of the protein, which can lead to a change in the course of a patient’s disease. Undruggable proteins generally don’t have large pockets on their surfaces. Instead, they look relatively smooth and featureless, from the perspective of a small molecule drug.
Q: Is there any hope of being able to make drugs that affect these proteins, and if so, what kind of diseases would these be useful for?
B.R.S.: The majority of proteins are considered undruggable, and they control nearly every disease process, from many types of cancer to neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s diseases, to many other diseases. In terms of trying to tackle these critical proteins with drugs, there are a number of ongoing efforts. One approach is to create huge collections of candidate drugs and to use advanced robotic systems to rapidly test thousands or even millions of them to see if any can be found that affect undruggable proteins. A second approach is to design drugs using sophisticated computer algorithms, trying to find a way to get a foothold on the surface of these proteins. Finally, another exciting strategy is to build larger molecules that have a better ability to interact with proteins, and then to solve the issue of how to deliver these larger molecules into a target tissue, such as a tumor. These are all current areas of active research. I am hopeful that some of these approaches will ultimately be successful.
Q: Some researchers in the field of systems biology argue that drugs of the future will consist of multiple drug molecules put together in a carefully tailored cocktail. Do you agree?
B.R.S.: I did favor this view for some time. In 1999, I founded a company called CombinatoRx that was focused on combining existing drugs in unexpected ways to create new medicines. For example, we found that an anti-parasitic drug combined with an anti-depressant had striking anti-cancer activity. At CombinatoRx, we screened millions of pairwise combinations of existing drugs against many different diseases. While we did find a number of strikingly synergistic combinations of drugs, these haven’t yet been turned into products that can benefit patients. So while I still think this is an interesting approach, the more important challenge is to unlock the huge reservoir of undruggable proteins, which would have a greater impact on disease.
Q: In the book, you write about Leo Sternbach’s serendipitous discovery of Valium. How does this relate to this problem of discovering new drugs today?
B.R.S.: In 1957, during a cleanup of his lab at the pharmaceutical company Roche, Sternbach discovered an old flask containing a chemical he had synthesized previously, but discarded for lack of interest. On a lark, he decided to have it tested for its anti-anxiety potential, a therapeutic area he had become interested in. The chemical, of an unknown identity, had striking anti-anxiety activity that was superior to the existing marketed drugs of that era. Within three years, Sternbach was able to figure out the identity of the chemical and had it approved for use in patients–a remarkable success, considering that drug development nowadays takes 10 to 15 years. This chemical was the first of the benzodiazepines, a class of drugs with a specific shape and structure that is powerful for treating anxiety. Some years later, Ben Evans and his colleagues at Merck discovered that benzodiazepine derivatives were also effective in treating other diseases and in interacting with other types of proteins. He suggested that this class of molecules is privileged, in the sense that it is especially effective at interacting with proteins and altering the course of disease. Other privileged molecular structures have since been discovered, and these molecules might be the key to addressing the undruggable proteins. Since these privileged compounds are so effective at interacting with numerous classes of proteins, they may be an effective starting point to look for new drugs against the supposedly undruggable protein targets.
Q: What else can be done to help improve the number of drugs discovered in the future?
B.R.S.: Only a small number of researchers have focused on the issue of the undruggable proteins–it is an understudied area. I would like to see a concerted effort by funding agencies and the biomedical community to address this grand challenge of our time. In addition, I think this is a great opportunity to educate students at every level about this fundamental scientific problem that has direct practical implications. By introducing the challenges associated with creating new medicines to curricula, we could teach students key aspects of chemistry, biology, pharmacology, and medicine, and hopefully stimulate the best minds to struggle with, and solve, this problem of the undruggable proteins. In the end, I do believe we will be successful, but we need to tackle this issue head-on, and with a serious commitment.