Finding the Right Drug for the Right Disease

Steven R. Smith, MD; Stephen J. Gardell, PhD


December 05, 2011

Editorial Collaboration

Medscape &

This feature requires the newest version of Flash. You can download it here.

Steven R. Smith, MD: Hello. I'm Dr. Steven Smith, Professor at Sanford-Burnham Medical Research Institute. Welcome to this segment of "Developments to Watch" from Sanford-Burnham and Medscape.

Joining me today is my colleague, Dr. Stephen Gardell, Associate Professor and Director of Translational Research Resources. Today's program will focus on key research efforts in screening compounds to identify new drugs as well as new uses for existing drugs and, importantly, how this research will affect clinical practice. Thank you for joining us, Stephen.

Stephen J. Gardell, PhD: It is a pleasure to be here.

Dr. Smith: Tell us a little bit about the challenges in identifying new drugs. Where are we now in the field and where might we be going?

Dr. Gardell: As you are aware, discovering and developing new drugs is extraordinarily challenging. In this day and age, it appears to have become even more challenging. There are a number of possible reasons for that. One is that a lot of people actually believe that perhaps all of the "low hanging fruit" has been picked, which means that what we are left with right now is a number of common, complex diseases. And complex diseases are exactly that. They are complex. So to be able to come up with what are going to be drugs that can prevent or treat these diseases is extremely challenging.

Another reason that has been cited with respect to increasing the difficulty or the challenges of drug discovery and development has to do with the regulatory agencies and the regulatory agencies increasing the bar with respect to safety. It is often cited especially in the lay press, although to what extent this is true, I am not sure.

Those are just 2 of the reasons that one could cite right now why it appears to be even more challenging.

The number of drugs in the pipeline has slowed -- slowed to a trickle is the way it has been described by some, and I have just provided you a couple of reasons why that may be so. One of the things that is important is that the pharmaceutical industry is now pulling back in terms of their resources that have been devoted toward some of the early-stage drug discovery.

This now represents an opportunity. It represents an opportunity for academic institutions and for research institutes such as the Sanford-Burnham Medical Research Institute -- not just us, but others have undergone a bit of a transformational change so that we can address this gap.

Clearly, there are a number of unmet medical needs out there and there is a dire need for what is going to be early-stage "leads" that can treat and prevent these diseases -- the drugs of tomorrow.

When I talk about some of the transformational changes that are taking place, let's start from the beginning -- "Drug Discovery 101."

It starts with a clever idea about what might be a root cause for the disease. More often than not, it involves a hypothesis where a particular protein that is involved is abnormal -- there is either too much, too little, or it may have an abnormal function. The quest that we are involved in is to be able to identify what is going to be a compound or a small molecule -- an agent that is going to be able to get in there, to be able to interact with our protein of interest, and be able to normalize its function. This quest is extremely challenging. There are billions and billions of small molecules in the chemical universe. The challenge for us is to be able to identify those precious few compounds that can interact specifically and tightly with the protein of interest and normalize its function. That is the essence of pharmacology.

Let's come back to the transformation. The first thing you need to do is to change the infrastructure. The Sanford-Burnham, as well as others, has undergone a change with respect to their scientific infrastructure so that now drug discovery is in its cross-hairs. To do this, you have to take in a wide breadth of different expertise as well as the equipment and the technology to allow you to engage in that particular pursuit.

It starts, as I said, with clever idea. You want to be able to identify chemical compounds that are the leads for the drugs of tomorrow. We engage in an activity known as high-throughput screening. We have large collections of compounds, or a library. For example, at the Sanford-Burnham, we have about 800,000 different chemical compounds in our library. We engage in a high-throughput screen, which is essentially assaying or testing each of those chemical compounds against our protein of interest.

What enables this is advances in 2 areas -- miniaturization and automation. Miniaturization is the concept of being able to run these tests or run these assays in test tubes. We are at the point right now where we can actually be doing all of these tests or assays in a little plastic dish that contains 1536 different wells in it. This is the equivalent of a test tube rack with 1536 test tubes. That is miniaturization. Now we come to the automation part -- we rely on robotic technology to allow us to be able to test, screen, or assay each one of these compounds against our protein of interest. The robots allow us to do this 24/7 in a high-throughput capacity.

To put this in prospective, I mentioned that our library is on order of about 800,000 compounds. It doesn't take us weeks. It doesn't take us days. We can actually screen all of these compounds against our target in a single day. That's high-throughput.

I should also point out that the Sanford-Burnham is one of four comprehensive screening centers in the United States that has been funded by the NIH [National Institutes of Health]. We are very fortunate to have this technology at our disposal. We also benefited from a benefactor, Conrad Prebys, who is a philanthropist from the San Diego area. A gift from Conrad Prebys coupled with the grant from the NIH has allowed us to establish our high-throughput screening center, the Conrad Prebys Center for Chemical Genomics.

Dr. Smith: This is remarkable technology within an academic institute. Tell us what the academic environment brings to the drug hunting. What is the special approach that academia can bring to these challenges that you mentioned a few minutes ago?

Dr. Gardell: The advantage that we can bring to the table is a deep understanding of the target and of the disease. That is clearly within the sweet spot of a research institute such as the Sanford-Burnham and other academic institutes as well. As I said, our strength is being able to achieve what is going to be a deep and detailed understanding of the mechanisms behind the disease process.

Dr. Smith: It's not a single-person pursuit, this drug hunting. It takes teams of people and a variety of different approaches, all the way through from the screening to optimization and the process that leads to the development of a drug.

Tell us a little bit about how people are working together in teams to tackle this, because it is a very complicated and challenging approach that cannot reside within a single person or even a single screening center. Tell us a little bit more about that.

Dr. Gardell: You are absolutely right. A multidisciplinary approach is required to be successful. Quite frankly, I think there are very valuable lessons to be learned from the pharmaceutical industry. They have been doing it. They have been successful. Before I joined the Sanford-Burnham, I was in the pharmaceutical industry for 20 years and many of my colleagues also have that kind of experience as well. There are important lessons that we learned when we were in that particular industry and we are applying those skills and expertise to where we are at right now.

You raise a very good point. I had spoken previously about the high-throughput screening and the robots. That is just the first step of the process. The fruits of that effort are something that we call "hits" -- those precious few compounds that interact with our protein target.

The next step is the progression of what we refer to as "hit-to-lead." That is where we get some of our other colleagues involved. We come back to the multidisciplinary aspects of this endeavor -- medicinal chemist, pharmacologist -- and tap into their expertise and their knowledge to take these original discoveries and make modifications to these compounds to come up with something that is going to be suitable and better. As we take it to the next step and start to run studies to evaluate its efficacy, we need this background information to convince ourselves that all the pieces are in place so that we can draw solid, firm conclusions about the experiments that are being run.

You are absolutely right to emphasize the part that this is a teamwork concept. Clearly, in order to be successful, you have to make sure that it is highly integrated.

Dr. Smith: There has been some discussion about taking old drugs and tuning them up, and maybe finding new indications or applications for those. Tell us a little bit about that effort. Why now are we looking into the past for some of these?

Dr. Gardell: There are a number of advantages to what has been described as repurposing drugs. One of the real advantages is that these are agents for which we have experience in man. Coming back to the hurdles that one encounters in drug discovery and development, the end-game of this is obviously to treat and cure human disease. We can run all the animal models that we want, but ultimately we need to get into man to assess whether our hypothesis is sound, and to assess whether this agent is as efficacious and as safe as our preclinical investigations would suggest. It is a high hurdle to get into man for obvious reasons. The regulatory agencies, and they are absolutely correct in this, are very demanding to ensure that no one is being put at risk.

One of the real advantages of repurposing drugs is that that hurdle has been overcome. They have passed the tests to be able to go into man and now there is experience. We know what to expect, so there aren't these critical concerns in terms of safety. For that reason, it expedites the process and, from the pharmaceutical company's point of view, it also makes it much cheaper.

Dr. Smith: The so called "de-risking" by knowing something about the compound already.

The relationship between Sanford-Burnham, the traditional pharmaceutical industry, NIH -- help me understand where you see Sanford-Burnham in that larger environment. How does Sanford-Burnham connect to the external world?

Dr. Gardell: One of the ways to be successful is to seek synergies. What the Sanford-Burnham and other research institutes and university labs do best, as I said before, is have a deep understanding of the disease. That is what we bring to the table. But to be able to move forward in the drug discovery and development process, we need to partner up with others who have the expertise in the other critical components of this particular process, the pharmaceutical industry for example. Due to the changing trends in the pharmaceutical industry, they are looking very keenly at some of the projects that are ongoing in the laboratories of the Sanford-Burnham and elsewhere. This is the breeding ground, if you will, where these ideas are being cultivated for what is going to be the new drugs of tomorrow. This is a very healthy relationship that is being built right now.

It is quite interesting. One of the growth areas in the pharmaceutical industry in the early stage of drug discovery is individuals who serve the roles of "scouts." At one time, this was largely as a result of the research that was being carried out in the pharmaceutical houses, internally, but a large amount of the resources that are being dedicated to the target identification and the target validation are now being sent out, to places such as the Sanford-Burnham as well as other universities and institutes. I think it is a very sound business decision. They recognize that, and as we look to the future, we are going to see even more of that.

What is absolutely essential, if there is a major theme here, it's that to be successful, we all share the same goal -- come up with what new drugs that are safe and efficacious to be able to treat and prevent the unmet medical needs that we have today. If we are going to be successful, it is as a result of partnering and being able to complement each other's strengths. Stay within your sweet spot, but reach out and interact in partnerships with others who can expand and contribute to what is going to be the overall effort.

Dr. Smith: These are big ideas, Steve, these external relationships coupled with internal competencies. Tell us a little bit more about areas of focus. Where is the Sanford-Burnham going? What is the emphasis or focus point at this point in time in this process?

Dr. Gardell: First and foremost, the one thing that continues to be an important thrust of our efforts is a very deep understanding of the mechanisms of disease. We have done that for many, many years and we will continue to do that. I have already spoken about one initiative, drug discovery. Another initiative that has gained considerable traction is translational research. Translational research, as you know so well, is being able to take the discoveries that are made in our laboratories and advance them to test their potential clinical utility. The so-called "bench-to-bedside" -- although it is equally important to go from bedside-to-bench. One of the things we are particularly excited about, something you know so well because you are the Director of the Translational Research Institute, is to be able to build that bridge between the discovery labs and the patient-oriented research. That is a resource that holds tremendous promise in terms of being able to accelerate the advancement of the discoveries that are coming from our lab.

Dr. Smith: That gets back to this emphasis that you mentioned a few minutes ago about understanding the fundamental basis of disease. That is an area where, oftentimes, we are struggling with understanding whether a particular target is relevant to these common chronic diseases that are on the uptick right now. This focus on translational research -- it is more than just clinical research. It has other steps, like animal models. Talk a little bit about what that continuum from bench-to-bedside looks like.

Dr. Gardell: You are absolutely right. As I said before, there is reciprocity in terms of the flow of information. We have information from the discovery labs that are advancing to the patient-oriented researchers and vice-versa. You mentioned the concept of animal models. We invest considerable time and energy exploring animal models as surrogates for human disease. In fact, perhaps one of the issues that we all wrestle with right now is the validity of those models. There is no such thing as a perfect animal model for human disease.

That's what makes the patient-oriented research so critical. We can generate all of these ideas, all of these hypotheses using our animal models, but ultimately we need to be able to test our ideas in man at the earliest opportunity that we can.

Dr. Smith: Let's go back a little bit and talk about the challenges of drug hunting, of finding from these billions of chemical opportunities, the 1 or 2 hits that can lead to a drug. What can clinicians look for in the near-term future? We talked about the decline in the number of good drugs coming through into clinical testing. Tell us what the future looks like from the clinicians' view of drug hunting.

Dr. Gardell: As I look to the future in terms of what clinicians can expect, I think it is going to be able to make better informed decisions. We want to be able to identify the right drug at the right dose for the right person. That is where we are going now in our drug discovery efforts. With this information in hand, we and the clinicians, when these drugs are launched, are going to be able to do a better job treating or preventing the disease that patients are faced with on a day-to-day basis.

Dr. Smith: So more of personalized or segmented population as opposed to a broad product profile. We are really talking about individualizing or personalizing therapy. That is part of this future that you see.

Dr. Gardell: Absolutely, the concept that one drug fits all is clearly outdated. It is just not outdated, it is just wrong. One of the things that we all appreciate right now is that the diseases we are trying to conquer are very heterogeneous. People are heterogeneous. Diseases are heterogeneous. If we are going to make an impact, we have to be able to stratify the patients so that we can recognize which patients should receive which therapy. You are absolutely right, personalized medicine is not just a concept -- it is truly becoming a reality. Much of the research that we are doing at the Sanford-Burnham is trying to make that a reality.

Dr. Smith: That was a very interesting topic. Thanks, Stephen, for participating in this program. We would both like to thank you for joining us today. I hope you will join us for additional programs in the "Developments to Watch" series on Medscape.