Joseph Salvino, Ph.D., medicinal chemist and professor in the Molecular & Cellular Oncogenesis Program and scientific director of the Molecular Screening & Protein Expression facility at The Wistar Institute, spent more than 20 years in the pharmaceutical industry’s drug discovery before coming to Wistar. Dr. Salvino collaborates with many Wistar scientists on programs to help identify novel small molecule lead compounds that could evolve into future drugs.
Here at the intersection of biology and chemistry is where Dr. Salvino and his team work best. Their medicinal and synthetic chemistry skills complement our investigators’ biology expertise. It’s a process wherein Dr. Salvino helps to optimize a hit compound our Wistar scientists identified or tries to identify a new lead compound for an interesting new target.
When Wistar scientists want to identify a compound that can produce a certain desired effect, Dr. Salvino works to optimize that compound’s ability to achieve its target effect. These early-stage compounds that show promise are called “hits,” and Dr. Salvino investigates these hits in a variety of biochemical settings.
Dr. Salvino’s expertise is in optimizing early-stage hits by improving target binding affinity and functional activity. His aim is to increase a compound’s biological potency and improve drug-like properties. To achieve this goal Dr. Salvino works closely with biologists to understand the molecular target. He focuses on how a small molecule will engage the target to elicit a biological response.
This crucial foundational research is the bedrock of the drug discovery process. It’s here that assays are developed with the throughput to support iterative medicinal chemistry optimization efforts that can quickly evaluate twenty or so compounds in a few days. The goal of lead optimization is to identify a suitable compound that could become a therapy to treat cancer and other disease. This is the compelling fundamental work that Wistar basic researchers accomplish before a drug discovery company considers translating what Wistar scientists have identified and potentially converts a Wistar discovery into a drug useful in health care.
As Wistar’s medicinal chemist, describe how you fit into Wistar’s scientific efforts?
I work in collaboration with Wistar scientists and scientists at neighboring universities to help identify a series of compounds suitable as a pharmacological means to modulate their target of interest. My job is to identify a suitable compound, part of a “hit-to-lead” series usually identified from a screening campaign, to test pharmacologically the effects of small molecule treatment both in vitro and in vivo.
In a lay friendly way tell us your process working with the scientists.
We work with other scientists by identifying and improving on small molecules that engage their protein target of interest. These small molecules may inhibit, stimulate, or degrade their protein and be biologically active in a cell expressing their protein, or where their protein is the cause for the disease we are trying to treat. My team needs to learn as much as we can about the molecular target from our collaborator.
We work with many Wistar investigators—typically those who are looking to identify or improve on a small molecule as a potential therapeutic agent for a disease related to their target. Often the investigator has already identified a small molecule to test their hypothesis. My team works in collaboration to improve or develop a new molecule, focusing on improving selectivity, potency, or its in vivo drug-like properties.
The Wistar Institute Molecular Screening & Protein Expression Core is under my direction. This group can develop assays that typically can be run in a plate-based format to provide a high-throughput approach to support our medicinal chemistry efforts. For example, when medicinal chemists are trying to identify an optimized compound, we need to synthesize and evaluate 10-50 different analogs that are related but have slight differences in their structure. We do this to probe for “structure activity relationships”—the changes required to improve binding affinity to a protein target or to improve its functional activity. Both binding affinity and functional efficacy are very important to optimize a molecule, even though its functional efficacy is what a biologist wants to study.
Interestingly, a typical drug discovery effort from a pharmaceutical company requires the synthesis of about 2000-3000 compounds per target to identify a development candidate.
How do you start working with scientists?
We start to work together because of a common interest in a target or a disease, such as treatment of melanoma, ovarian, or breast cancer or EBV associated cancer, or others. We normally start collaborating because of our common interests and complementary skills.
What aspects of your work do you like most?
I enjoy the interface between chemistry and biology. I love finding new compounds with interesting biological activity in collaboration with my colleagues, especially for interesting new targets. I like working with the screening core to help develop new methods to test compounds. We spend a lot of time synthesizing chemical probes, such as a binding probe, which greatly facilitate assay development. A binding probe, or also sometimes called a tracer, is used in a competitive binding assay, where an unlabeled compound will compete for binding with the tracer. For this type of study, we can determine the binding affinity of an unlabeled test compound.
Wistar does not make drugs or therapies but advances discoveries that can move into drug discovery as future therapeutics.