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A New Prescription for Drug Discovery

By Bill Snyder
January 2011

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Researchers at Vanderbilt University are busy building the pharmacy of the future. On its shelves may be:

• New medications for schizophrenia and Parkinson’s disease, and the first drug treatment for Fragile X syndrome;

• A drug that can stop a particularly vicious form of breast cancer in its tracks;

• A replacement for acetaminophen that can be given in higher, more effective doses without causing liver damage; and

• A new way to treat obesity and diabetes by “tickling” a receptor in the brain.

These bold ideas are being pursued today at Vanderbilt, thanks to a unique recipe for drug discovery that blends bench science with clinical medicine and academia with industry.

While there’s no guarantee that any of these potential drugs will survive the tortuous road to market, Vanderbilt scientists and their physician colleagues believe they are on the threshold of a new era of innovation.

“I think we’re right on the cusp of real breakthroughs because our scientific understanding has increased dramatically,” said Jeffrey Conn, Ph.D., director of the Vanderbilt Program in Drug Discovery (VPDD), which explores new treatments for neurological and psychiatric diseases.

“If we are able to overcome the technical hurdles and if we can find small molecules that inhibit these targets that we’re pursuing,” added Stephen Fesik, Ph.D., a leader of Vanderbilt’s cancer drug discovery effort, “we could have a dramatic effect on cancer therapy, effects that won’t just give you a slight increase in lifespan … but would actually lead to cures.”

“One thing that’s unique about Vanderbilt now is we’ve built the infrastructure to look just like a pharmaceutical company,”  said Craig Lindsley, Ph.D., director of Medicinal Chemistry in the VPDD who, like Conn, came to Vanderbilt from Merck. “We have all of the instrumentation and technology that you’d find at a Merck or a Pfizer or a GlaxoSmithKline.”

Vanderbilt's team approach to discovery science includes heavy hitters (left to right) Stephen Fesik, Ph.D., Gary Sulikowski, Ph.D., Jeffrey Conn, Ph.D., and Craig Lindsley, Ph.D. The four recently participated in a round table discussion of the current state of biomedical research in the United States and Vanderbilt's role in moving it forward. Photos by Joe Howell.

Vanderbilt's team approach to discovery science includes heavy hitters (left to right) Stephen Fesik, Ph.D., Gary Sulikowski, Ph.D., Jeffrey Conn, Ph.D., and Craig Lindsley, Ph.D. The four recently participated in a round table discussion of the current state of biomedical research in the United States and Vanderbilt's role in moving it forward. Photos by Joe Howell.

Vanderbilt, of course, is not capable of bringing products to market, and later-stage clinical trials of drugs discovered here probably will be conducted elsewhere.

But drug companies have struggled lately to fill the “pipeline” with new compounds that potentially can solve important problems in human health. At the same time, many firms are downsizing their research operations, laying off scientists and tightening their belts, as patent protection ends for some of their best-selling brand name products.

“Changes in reimbursement for drugs will have a huge impact on the availability of new drugs,” noted Nancy Brown, M.D., who chairs the Department of Medicine and is acting director of Clinical Pharmacology at Vanderbilt.

It can cost over a billion dollars to bring a drug to market. If it becomes more difficult to recoup that investment, Brown said, companies “either have to become more efficient in developing drugs and predicting which drugs will make it, or new drug development will decline – and has.”

This is where Vanderbilt researchers can help.

“Ultimately it takes the pharmaceutical industry to fully develop and market a drug,” said Conn, the Lee E. Limbird Professor of Pharmacology. “Anything we can do to increase the probability of success … in taking those drugs to market (will) have an impact on patients and the economy.”

The National Institutes of Health, which funds the major portion of biomedical research in the United States, “is really pushing on us now to do drug discovery in the academic environment,” added Lindsley, professor of Pharmacology and Chemistry. “It’s a whole new paradigm of NIH-sponsored research, and Vanderbilt, I think, is uniquely positioned to capitalize on this whole next wave.”

Consider these examples:

Dimmer switches in the brain
Conn, Lindsley and their colleagues have pioneered a novel approach to treating neurological and psychiatric disorders using compounds called “allosteric modulators.”

Rather than turning a receptor “on” or “off” (which is what traditional drugs usually do), allosteric modulators “tune” the receptor function up or down, like a dimmer switch in an electrical circuit.

The researchers have discovered promising candidates for treating a wide range of disorders including Parkinson’s disease, schizophrenia and Fragile X syndrome.

An estimated 1.5 million Americans have Parkinson's disease, a progressive brain disorder characterized by uncontrollable muscle tremors and rigidity. It is caused by the death of nerve cells in a specific brain region that produce the neurotransmitter dopamine.

Dopamine replacement therapy can relieve symptoms, but it also causes side effects and eventually becomes less effective as the disease progresses.

With support from the NIH and the Michael J. Fox Foundation for Parkinson’s Research, the Vanderbilt researchers have identified two drug-like molecules that may avoid the limitations of current therapy by acting on a brain receptor that binds a different neurotransmitter, glutamate.

Schizophrenia affects more than 2 million Americans. Current therapy can reduce hallucinations and delusions but is less effective in relieving cognitive symptoms and social withdrawal.

With funding from the NIH and Janssen Pharmaceutica, a Johnson & Johnson company, Conn’s team is testing ways to “tune” a specific glutamate receptor in order to alleviate all symptoms of schizophrenia.

Fragile X syndrome is the most common inherited form of intellectual and developmental disabilities, and the most common genetic cause of autism.

In collaboration with Seaside Therapeutics in Cambridge, Mass., the researchers are trying to “tune down” signaling through two different brain receptors – one involved in learning and memory, and the other associated with autistic and other behavioral symptoms of Fragile X syndrome.

So far, the researchers have shown that the compounds penetrate the blood-brain barrier and have the desired effects in animal models of each of these diseases. If they pass further animal testing and toxicity studies, Lindsley and Conn predicted they may be ready for testing in humans by early 2012.

“The unique thing about these academic drug discovery efforts at Vanderbilt is that novel mechanisms are being explored, and the drugs that result have the promise of fundamentally changing how diseases such as schizophrenia, Alzheimer’s, Parkinson’s and autism are treated,” said Heidi Hamm, Ph.D., the Earl W. Sutherland Jr. Professor of Pharmacology and chair of the Department.

“Early studies are hinting that the compounds may not only treat the symptoms of these diseases, but actually alter the course of the pathology.”

‘Hit molecules’ for cancer
Fesik, the Orrin H. Ingram II Chair in Cancer Research, is developing new approaches to target proteins that currently are considered to be “undruggable.”

Protein-protein interactions play a central role in nearly all signaling processes in cells, including cancer cells, but targeting these proteins will require a new set of tools beyond those used in traditional drug discovery.

Fesik, who came to Vanderbilt in 2009 from Abbott Laboratories, is using fragment-based methods – screening small chemical fragments for their ability to bind to small pockets on a protein target.

He and his colleagues then obtain and examine crystal structures of the “hit molecules” bound to their targets. This information can show them how to link the fragments into drug-like compounds with the “right pharmaceutical properties to move forward,” he said.

In August 2010, Fesik became the first Vanderbilt scientist to receive a prestigious NIH Director’s Pioneer Award, which will provide $2.5 million in direct costs over the next five years to support his work.

Fesik also is part of Vanderbilt’s cancer drug discovery program, established in 2009 by a two-year $4.7 million NIH “Grand Opportunities” grant funded by the federal Recovery Act.

The Vanderbilt Molecular Target Discovery and Development Center, a joint effort of the Vanderbilt Institute of Chemical Biology (VICB) and the Vanderbilt-Ingram Cancer Center, initially will hone in on “triple-negative” breast cancer, a particularly deadly form of the disease.

The most successful treatments for breast cancer target tumors that “express” receptors for the hormones estrogen and progesterone and for the human epidermal growth factor receptor 2 (HER2). Because “triple-negative” breast cancers don't express any of these receptors, they are difficult to treat, and account for 25 percent of all breast cancer deaths.

Researchers are searching for genes – and the proteins they encode – that “drive” different subtypes of the cancer. Then they will try to fashion compounds that can block the proteins and kill the cancer cells.

“This is really personalized drug discovery,” said VICB director Lawrence Marnett, Ph.D., Mary Geddes Stahlman Professor of Cancer Research and principal investigator of the Grand Opportunities grant. “We think (it) represents the model for the future.”

Gary Sulikowski, Ph.D., Stevenson Professor of Chemistry and associate director of the VICB Chemical Synthesis Core, is leading another cancer drug discovery effort. His group has synthesized several anti-tumor antibiotics isolated from various soil microorganisms.

Sulikowski also is co-principal investigator with Alex Waterson, Ph.D., research assistant professor of Pharmacology, of the Vanderbilt Chemical Diversity Center, part of a National Cancer Institute effort to spur the discovery and development of new cancer drugs.

The partnership between the School of Medicine and Department of Chemistry “really opens up new approaches,” Sulikowski said.

Breaking the dose ‘ceiling’

Acetaminophen, the ingredient in Tylenol and similar drugs, is the most commonly used fever and pain reliever in the world. In high doses, however, it is toxic to the liver.

Every year in the United States, acetaminophen overdose causes more than 50,000 cases of liver toxicity – and more than 400 deaths, said John Oates, M.D., the Thomas F. Frist Sr. Professor of Medicine and professor of Pharmacology.

Were it not for the 4-gram-a-day dose ‘ceiling’ imposed by toxicity, acetaminophen could do more than ease pain and lower fever.

Recent animal studies conducted by Oates and his colleagues suggest that in higher doses the drug could prevent kidney failure following traumatic injuries, and neurological damage following bleeding in the brain.

Myoglobin is a protein that transports oxygen to the muscle, just as hemoglobin does in the blood. When muscle is crushed, it releases myoglobin, which travels to the kidneys and, through a reaction called lipid peroxidation, generates free radicals and other kidney-killing products.

“In a situation like (last year’s) earthquake in Haiti … they had to go to the medieval extreme of amputating limbs that were crushed in order to prevent kidney failure,” Oates noted. Similarly, bleeding in the brain can, via lipid peroxidation, cause stroke-like damage.

Oates, who founded Vanderbilt’s Division of Clinical Pharmacology, and longtime colleague L. Jackson Roberts II, M.D., the T. Edwin Rogers Professor of Pharmacology, wondered if they could design a replacement for acetaminophen – a drug that blocks lipid peroxidation without damaging the liver.

They joined forces with Stevenson Professor of Chemistry Ned Porter, Ph.D., to do just that.

“I have a high level of confidence … that we will have some successful compounds because we’re working on a mechanism we understand for both the effectiveness and the toxicity,” said Oates, who has applied for NIH funding to continue the work. “We know enough about those to know that we can pull them apart.”

(from left) John Oates, M.D., who founded the Division of Clinical Pharmacology, Heidi Hamm, Ph.D., chair of the Department of Pharmacology, and Gordon Bernard, M.D., director of the Vanderbilt Institute of Clinical and Translational Research, exemplify the breadth of Vanderbilt’s commitment to drug discovery. Photos by Dean Dixon and Steve Green.

(from left) John Oates, M.D., who founded the Division of Clinical Pharmacology, Heidi Hamm, Ph.D., chair of the Department of Pharmacology, and Gordon Bernard, M.D., director of the Vanderbilt Institute of Clinical and Translational Research, exemplify the breadth of Vanderbilt’s commitment to drug discovery. Photos by Dean Dixon and Steve Green.

Oates credited an $180,000 Vanderbilt pilot grant awarded in 2007 with accelerating the research and moving it to a more advanced drug development stage. “If we’d not had that, we would be proceeding at a molasses pace,” he chuckled.

Tickling the appetite receptor
Drugs prescribed for the twin epidemics of modern life, obesity and type 2 diabetes, are among the biggest sellers in the pharmaceutical industry. According to some estimates, they will exceed $50 billion in annual worldwide sales by 2015.

A class of diabetes drugs called GLP-1 analogs has been particularly successful in controlling blood glucose while helping patients maintain, or even lose weight.

GLP-1 (for glucagon-like peptide 1) is a hormone that stimulates insulin secretion in response to elevated blood glucose levels, while decreasing secretion of glucagon, which opposes insulin action. Once glucose levels are normal, the GLP-1 effect shuts off.

The peptide also slows gastric emptying in the stomach and reduces appetite by acting on the satiety centers in the brain, thereby helping to control weight. “Analog” drugs, like Byetta, that bind to and activate the GLP-1 receptor can amplify the natural hormone. But they are not without side effects, including nausea and vomiting.

Kevin Niswender, M.D., Ph.D., and David Weaver, Ph.D., director of Vanderbilt’s high-throughput screening facility, wondered if they could develop an allosteric modulator to “tickle” the receptor in a way that preserves or even enhances the benefits of GLP-1 analogs while limiting their side effects.

They have begun to search for small molecules that bind to and activate the receptor in unique ways. The compounds will be tested in isolated pancreatic islets to see whether they affect insulin secretion.

In the end, “tickling” the receptor may be no better than simply switching it on. But the researchers hope their study will reveal more of what GLP-1 is doing in the brain and how the GLP-1 receptor works.

Could drugs that improve insulin and GLP-1 signaling in the brain strengthen one’s preference for low-fat, low-carbohydrate foods over less healthy choices?

Obesity is not “a defect in the push-away-from-the-table muscle,” said Niswender, assistant professor of Medicine and of Molecular Physiology & Biophysics.“It’s a very potent neural circuitry. It’s not just the appetite circuits, but it’s the mood circuits, it’s the cognition circuits, it’s the impulsivity circuits that are all colluding against somebody’s efforts to make good decisions and ultimately lose weight.”

‘Valley of death’
In today’s economically strained environment, companies are reluctant to invest in high-risk drug discovery projects – because most won’t pan out.

Of the thousands of “drug-like” compounds identified each year, only a few hundred will show sufficient activity to enter pre-clinical testing in cell cultures and animals.

Only a handful of these will meet the criteria for testing in humans. They must be absorbed by the body and reach their target tissue at a high-enough concentration to do the job, and they must be effectively eliminated by the body so they don’t reach toxic levels.

A final challenge is to cross what is called the “valley of death.”

That’s “where the drug has to undergo a number of studies to prove that it’s reasonably safe to give to human beings,” said Gordon Bernard, M.D., associate vice chancellor for Research and director of the Vanderbilt Institute for Clinical and Translational Research.

Increasingly these studies are being outsourced to academia. However, they’re costly and scientifically uninteresting, and this is where many drug candidates fall by the wayside. “Unless we can come up with a clever strategy to fund these requisite studies, I fear a lot of these opportunities will be lost,” warned Marnett.

Protecting the intellectual property (IP) rights of a discovery is equally important. “If there is no IP, no matter who develops an idea … nobody will make the $300 million investment to get it to people,” Niswender explained.

Vanderbilt’s drug discovery program is flourishing in part because the university’s attorneys and technology transfer officials have been willing to “think out of the box,” to move outside of the “comfort zone” of the traditional academic setting, Conn added.

“It’s … the willingness to take risks … to move into new areas in terms of IP and negotiating agreements with companies, and not allowing the complexity of legal issues that are uncharted territory for most universities to stop you,” he said.

“That’s what really has to continue at Vanderbilt.”



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