Denny Sanford and Malin Burnham are the latest in a long line of partnerships to advance the Institute’s important work, starting with co-founders Dr. William and Lillian Fishman.
In fact, collaboration is one of Sanford-Burnham’s most cherished values and has led to many successes in the laboratory. Biologists, chemists, pharmacologists, physicists, engineers and others routinely cross disciplinary boundaries to find solutions to pressing medical problems.
As Sanford-Burnham enters a new era of accelerated research, one area where this collaborative spirit will lead to new successes is drug discovery. Quite often, diseases can be linked to aberrant proteins that may be too active or not active enough. Much of the work being done at Sanford- Burnham seeks to identify these problem proteins and understand how they contribute to disease.
With the creation of the Conrad Prebys Center for Chemical Genomics (Prebys Center), scientists were given a new tool to find chemical compounds (also called small molecules) that could beneficially alter the behavior of a protein. Sometimes, these small molecules become research tools to learn how a protein’s function affects an organism or the progress of a disease. And sometimes, a small molecule will be developed into a new medicine.
Making Cells Behave
Dr. Maurizio Pellecchia.
The outside surfaces of cells contain proteins called receptors, which work by binding with other molecules called ligands. When a ligand attaches, the receptor is activated and sets off a cascade of activity within the cell. This is one of the fundamental ways the body talks to cells.
For many years, Elena Pasquale, Ph.D., has studied a family of receptors called Eph. These receptors play a major role in early development but are also implicated in the uncontrolled cell growth associated with cancer. Dr. Pasquale’s laboratory was among the first to identify several Eph receptors and their ligands (called ephrins), describe how they function and develop ways to control them.
“Because these receptors are so prevalent in cancer cells, they could be an excellent target for treatment,” says Dr. Pasquale. “For example, we could use a molecule that binds to them to deliver a therapeutic drug. These over-expressed receptors could become a doorway to bring in medication.”
Dr. Pasquale is working closely with Maurizio Pellecchia, Ph.D., to attach Eph ligands to anti-cancer drugs, like Taxol.
“We believe this could be a very effective strategy,” says Dr. Pellecchia. “Our data strongly suggest that these drug conjugates effectively deliver the chemotherapeutic agent to Eph cancer cells. This technology is likely applicable to a variety of solid tumors that over-express the Eph receptor, including prostate, lung, breast and ovarian cancers.”
Building a Better Molecule
Computer model of small molecule compound (top of image) binding to Eph protein.
The Prebys Center screens thousands of small molecule compounds against biological material to find a handful of hits—molecules that can alter a protein’s function. But that’s only the beginning of the story. Medicinal chemists, like Nicholas Cosford, Ph.D., take those molecules and improve (optimize) them. Small molecules work by binding to a specific part of a protein, so making the bind tighter could improve the molecule’s effectiveness. There are other properties to consider. Does the molecule stay in the body long enough to be effective? Is it safe? Does it attach only to the target protein or is it binding to other proteins, which could lead to unwanted side effects?
Dr. Cosford optimizes a compound by strategically adding atoms to the original molecule, a process that combines science and experience. Once a molecule has been altered, it must be retested against biological material to determine if its properties have improved. This can be slow work, but Dr. Cosford is pioneering a new technology, called microfluidics, that accelerates molecular redesign.
“We have compressed several steps down to a single process,” says Dr. Cosford. “What used to take a couple of days, we can now do in about 20 minutes. This is a powerful way to accelerate drug discovery.”
Dr. Cosford and Dr. Pasquale are collaborating to improve molecules that interfere with the interaction between Eph proteins and the ephrin proteins that bind to them. If successful, their work will create compounds that further help Dr. Pasquale unravel the mysteries behind Eph/ ephrin interactions. Also, since protein/protein interactions are abundant in cells, finding ways to obstruct (or enhance) them might open doors in other disease research.
“If we can understand how to use small molecules to disrupt protein/protein interactions, then we have the opportunity to treat diseases in new ways,” says Dr. Cosford. Drs. Pasquale and Cosford hope that at least one of the compounds they are testing will have strong drug-like properties that would merit further testing, possibly leading to preclinical and clinical trials. Their efforts could result in new cancer treatments down the road.