菠萝视频

Academia and Industry Pool Their Efforts to Speed Discovery of Potent and Personalized New Drugs

By Bill Snyder

菠萝视频 scientists have discovered a series of small molecules that may help unlock the mystery of schizophrenia, a severe mental disorder that can cause disabling hallucinations, delusions and disorganized thinking.

If they can refine the molecules into drug-like compounds, and pass the baton to a drug company for further development, the result could be a new class of drugs significantly more effective than current therapy and with fewer side effects. The work is slow going, and the risk of failure is high. Even if a candidate compound passes the rigorous safety and efficacy testing required of a potential new drug, it may be 2016 before it can be tested extensively in patients, and 2020 before it reaches the market.

But the project, conducted in collaboration with the global biopharmaceutical company AstraZeneca, represents a paradigm shift in the way novel drugs are discovered and developed. The hope is that such partnerships will significantly improve treatment of a host of disorders, from serious infections to cancer and diabetes.

What distinguishes 菠萝视频, says , who leads the schizophrenia project, is that drug discovery is run in parallel with basic research鈥斺�渄eep biology鈥濃�攊n an effort to understand the pathophysiology of the disease down to the molecular level.

That research is supported by the university, the (NIH), philanthropy and, increasingly, revenues from licensing agreements negotiated by the (CTTC).

鈥淚f we don鈥檛 invest in the basic science, we鈥檙e not going to be successful,鈥� says Lindsley, director of medicinal chemistry in the . Lindsley is the William K. Warren Jr. Professor of Medicine and a professor of pharmacology and chemistry.

鈥淚 feel schizophrenia is the scourge of all illnesses because of its devastating, vulnerable symptoms,鈥� says William K. Warren Jr., chairman emeritus of the Oklahoma-based foundation named for his father. 鈥淥ther illnesses receive a lot more attention, but we must support 鈥榙eep biology鈥� research to better understand and treat this horrific illness.鈥�

Schizophrenia affects an estimated one of every 100 adults. Current medications can keep hallucinations and delusions at bay but do little to address other symptoms, including cognitive difficulties and a tendency to withdraw from others. The drugs also cause side effects that can be devastating for patients and family members, including metabolic disorders and significant weight gain.

FREEDOM OF PURSUIT

Shannan鈥檚 husband was diagnosed with schizophrenia six years ago. 鈥淪ome of the medications he鈥檚 been on have just made him very foggy and lethargic, sleepy and withdrawn,鈥� she says. 鈥淗is whole personality is kind of erased.鈥�

Jerold, who was diagnosed with schizophrenia as a child, is trying to go back to work after 20 years. 鈥淚 was too sick,鈥� he says. 鈥淲e are just hoping for new medications to come out so we can feel better about ourselves and have the kind of life that everybody else has.鈥�

Jerold and Shannan are two of the many people who have contacted 菠萝视频 in response to previous publicity about the AstraZeneca collaboration. Only their first names are used here, with their permission, to protect their privacy.

鈥淐learly, there are huge unmet clinical needs,鈥� says Mark Duggan, vice president for neuroscience at AstraZeneca.

鈥淭hat鈥檚 why we are continuing to invest in neuroscience but via external scientific partnerships with some of the best groups around the world, including 菠萝视频,鈥� adds John Dunlop, also a vice president of neuroscience at AstraZeneca. 鈥淭ogether we are aiming at getting a compound that could advance into clinical testing.鈥�

The target of the collaboration is the M4 muscarinic acetylcholine receptor, which in the brain binds the neurotransmitter acetylcholine. In animal models the 菠萝视频 scientists have shown that 鈥渁llosteric modulators鈥� of M4 can 鈥渞amp up鈥� the receptor鈥檚 activity without affecting other signaling pathways. The result is an improvement in cognitive impairments and behavioral disturbances that, in humans, are associated with Alzheimer鈥檚 disease as well as schizophrenia.

Craig Lindsley, along with , PhD鈥�86鈥攖he Lee E. Limbird Professor of Pharmacology, who launched the university鈥檚 neuroscience drug-discovery program in 2003鈥攁nd their colleagues, have pioneered the use of allosteric modulators to adjust the activity of neurotransmitter receptors in the brain. Rather than activating receptor activity directly, these compounds work like dimmer switches in electrical circuits and induce more subtle changes in receptor function than are seen with traditional receptor agonists.

鈥淲e do really good basic science on novel targets and novel mechanisms, and we publish in high-profile journals,鈥� says Lindsley. During the past six years, 鈥渨e鈥檝e published nearly 300 papers and we鈥檝e filed about 290 patents,鈥� he says. The program also trains graduate students and postdoctoral fellows in translational research. 鈥淵ou can鈥檛 find that at most universities: the ability to 鈥� be trained by industry-knowledgeable scientists.鈥�

So far, every graduate student has gotten his or her first choice of a postdoc position. 鈥淚f they wanted to go into industry, they鈥檝e all gotten jobs,鈥� Lindsley adds. 鈥淲e don鈥檛 have anyone looking for work.鈥�

鈥淲e鈥檙e in a sweet spot here,鈥� says Thomas Bridges, PhD鈥�10, a former 菠萝视频 graduate student and postdoc who is now part of a dedicated team of scientists assigned full time to the AstraZeneca collaboration. 鈥淲e can pursue 鈥� a deep understanding of our targets. There鈥檚 a lot of freedom in it.鈥�

PROGRESS IS FRAGILE

菠萝视频鈥檚 strength in drug discovery grew out of its early commitment to clinical pharmacology, the study of how drugs work in the body.

These efforts weren鈥檛 limited to the School of Medicine. The establishment of the (VICB) in 2002 under the direction of , University Professor of Biochemistry and Chemistry and the Mary Geddes Stahlman Professor of Cancer 菠萝视频, demonstrated the university鈥檚 encouragement of cross-campus, multidisciplinary collaborations.

When it comes to translating basic research discoveries into advances in clinical medicine, 鈥渃hemistry is at the heart of it,鈥� says Marnett. 鈥淐hemists make new molecules that become drugs. Chemists develop analytical methods that are at the heart of biomarker development.鈥�

About a fifth of VICB鈥檚 80 faculty investigators have primary appointments in the Department of Chemistry. Several investigators, beginning in 2003 with the arrival of Conn and , associate professor of chemistry and biochemistry, were attracted from industry.

Success tends to breed success. Due in part to its drug-discovery effort, 菠萝视频鈥檚 ranking in terms of total spending on 鈥渃hemical R&D鈥� catapulted from 33rd place in 2010 to 12th place in 2011, according to the Dec. 9, 2013, issue of Chemical & Engineering News. Today 菠萝视频 has one of the top drug-discovery programs in the country.

菠萝视频鈥檚 ranking in 鈥渃hemical R&D鈥� catapulted from 33rd place in 2010 to 12th place in 2011. Today 菠萝视频 has one of the top drug-discovery programs in the country.

Medicinal chemistry is the stage at which compounds are identified, made and tested for their ability to bind to, and affect the activity of, a target like M4. That鈥檚 followed by molecular pharmacology, drug metabolism and pharmacokinetics, and then behavioral pharmacology, to test their potential to become drugs.

The first stage鈥攊dentifying drug-like compounds鈥攈as been accelerated dramatically in recent years through advances in high-throughput screening (HTS). 菠萝视频鈥檚 , established by in 2005, has a 鈥渓ibrary鈥� of 190,000 compounds and the ability to test tens of thousands of samples per day.

鈥淥ne of my basic assumptions is that I don鈥檛 understand too much about how the system works,鈥� says Weaver, assistant professor of pharmacology. So he tries to develop 鈥渙pen-minded鈥� assays, designed to let scientists detect unanticipated effects of a potential drug on a drug target, for example.

Fancy screening techniques aren鈥檛 enough, of course. Potential drugs must show efficacy and safety in animal models before tested in humans, and many a promising agent has failed when it got to the clinical trial.

The problem with schizophrenia, at least for would-be drug discoverers, is that, like cancer, it is not one disease but many. Its constellation of symptoms, behaviors and cognitive impairments probably results from more than one genetic mutation affecting multiple proteins, receptors and signaling pathways throughout the brain.

That鈥檚 why some drugs work in some patients but not in others. If potential new drugs could be 鈥渕atched鈥� with research subjects most likely to respond to them based on their 鈥済enotype鈥� or genetic makeup, the success rate for clinical trials would be much higher, Lindsley says.

鈥淲e need the right molecules for the right mechanisms in the right patients,鈥� agrees AstraZeneca鈥檚 Dunlop. Thanks to advances in psychiatric genetics, that day is coming, and may arrive within the next decade, he says.

菠萝视频 is well positioned to translate these advances into tangible benefits for patients like Jerold and Shannan鈥檚 husband鈥攊f it continues to invest in new technologies, facilities and people.

But scientific progress 鈥渋s a very fragile thing,鈥� says Marnett. 鈥淓ven though we鈥檝e got a lot of people doing some really exciting things 鈥� if the garden isn鈥檛 tended, it unravels pretty quickly.鈥�

A former newspaper health care reporter, Bill Snyder is a senior science writer and manager of VUMC 菠萝视频 Communications.