Ever wonder how a new drug is discovered? Think of a key and a lock.
“The ‘key’ is a small molecule,” says Thomas “T.C.” Chung, Ph.D., associate director of the Mayo Clinic Center for Clinical and Translational Science Office of Translation to Practice. “You’re looking for a certain shape and geometry. The ‘lock’ is the protein target you’re interested in.”
Dr. Chung, a career long veteran of the drug discovery process, currently helps Mayo Clinic investigators translate clinical and research findings into new medical therapies for patients.
Searching for Keys
As Dr. Chung explains it, the protein target will be tied to a crucial step in the disease process and the key will either change the target’s shape, activity or distribution.
But you have to be careful. The key has to fit the lock in a way that makes it highly effective and very selective.
“If the key is highly potent, a very low amount will give you the effect you want,” says Dr. Chung. “Meaning you can take a small pill versus a ‘horse’ pill. And you want it to be highly selective to minimize toxicity and side effects. And third, you want it to be highly specific against molecular family members.”
Dr. Chung provides the example of a particular kinase, an enzyme within a family of five related kinases. These enzymes add phosphate groups to other proteins, modifying their behaviors. The new drug “key” will have to fit as closely as possible to this kinase to avoid interfering with the functions of other family members, or causing problems with out of family enzymes with different functions, like proteases which break apart proteins.
“So to find the right key,” says Dr. Chung, “researchers have to actually test many chemical compounds that represent the structural diversity and space of chemistry; hopefully a subset will map onto interesting biology.”
Huge chemical libraries are curated by academic, governmental, and industry groups. One of Mayo Clinic’s collaborators, Sanford Burnham Prebys Medical Discovery Institute (SBP), has a library of about 320,000 compounds according to Dr. Chung. The National Institutes of Health collection is about 385,000 chemicals, while pharmaceutical company GSK has one of the largest libraries with 3.2 million chemical compounds.
Sorting Through the Chemical Key Ring
When an investigator identifies a disease target (a potential “lock”), it can then be tested. One example is cyclophilin B. Mayo Clinic researchers found that this protein abounds in two types of nervous system tumors, glioblastomas and medulloblastomas. To find potential drug keys, Mayo Clinic partnered with an external group to test compounds that would bind to the cyclophilin B protein and stop tumor growth. After testing about 385,000 compounds, 314 were advanced to review and ultimately 99 were selected for testing. [Read the full story in Discovery’s Edge, “Mayo Plugs into Drug Discovery”]
Most new drug targets hit a wall when they get to this stage. Establishing a drug discovery group is very expensive. “I personally established one at SBP,” said Dr. Chung, who came to Mayo from SBP. “I spent greater than $20 million to help build their world-class drug discovery infrastructure and staff it with deep pharmaceutical experience, and transitioning it to a self-sustaining enterprise.”
Does It Work?
But if they do make it, drugs still have to work in cells and then in animal studies, a required step before human clinical trials. However, animal models may not predict what happens in the clinic, Dr. Chung says, and it’s one of the riskiest aspects when choosing to go forward with an experimental compound.
Once an experimental drug makes it through animal studies, it moves to safety studies (phase one human trials), and into trials that measure the compound’s ability to act on the disease step (phase two). At this point, only about 20 percent of experimental products remain. “The reasons for failure are usually other things like side effects,” says Dr. Chung.
If the key is a close match and the drug action outweighs the side effects, the new drug will make it through testing in a large group of subjects (phase three) and eventually to the pharmacy.
“The typical average cost of a compound from conception to marketing is roughly 1.3 billion dollars and it goes up every year,” says Dr. Chung. Programs like the Office of Translation to Practice aim to help bring that number down and get more therapies to market faster. “Everything is more complex and you need a team of people,” says Dr. Chung. “Putting together that team is what we’re trying to streamline, creating the infrastructure and leveraging our contacts.”
The goal? Ensure that Mayo Clinic continues to be the world leader in transforming discoveries into breakthrough treatments for unmet patient needs.
– Sara Tiner, August 4, 2016