$2.5 million NIH grant to help UB researchers remove guesswork from drug discovery

How can a drug be designed to only target proteins that are already switched off? Does whether a drug works depend on where its molecule fragments are linked together? Is drug potency being measured incorrectly?

These are the kinds of fundamental drug discovery questions that UB researchers will try to answer with the help of a $2.5 million Maximizing Investigators’ Research Award (MIRA) from the National Institute of General Medical Sciences, part of the National Institutes of Health (NIH).

The five-year project, led by David Heppner, Jere Solo Assistant Professor of medicinal chemistry, College of Arts and Sciences, seeks to take much of the guesswork out of drug discovery, a costly and time-consuming process with high rates of failure. 

“The vast majority of small molecule drug development programs are done by throwing as much against the wall as possible and seeing what sticks, yet waste accumulates and the cost goes through the roof,” says Heppner, the grant’s principal investigator. “We are trying to use chemistry to alleviate the guesswork in the development pipeline, thereby reducing costs and the time to new medicines.”

While the project’s findings will be relevant to virtually all drug targets, researchers will focus their work on protein kinases. These are a group of enzymes that regulate cell growth, so inhibiting them can potentially slow or stop the growth of cancer cells. 

Drugmakers typically test a compound’s ability to inhibit or turn off active kinases, yet active kinases are often in structural formations that are hard for compounds to bind to. It can sometimes be more effective to inhibit inactive kinases, preventing them from turning on in the first place. 

Heppner’s team has developed inhibitor compounds that can only bind to inactive kinases.

“The inhibitor compounds have unique properties that allow them to be selective toward one specific state; in this case the inactive state,” Heppner says. “We want to test their abilities against kinases’ inactive states so we know that we can shut them down more effectively.” 

The team will also research the placement of linker molecules. Fragment-based drug discovery involves creating compounds by linking fragments of different molecules together with another molecule, often called a linker. In a study published earlier this year, the team found that the point at which these fragments were linked together had a large effect on potency.

“We will continue to test how linker placement impacts our compounds’ ability to inhibit the kinase domain of the epidermal growth factor receptor, or EGFR, a key protein in non-small cell lung cancer,” Heppner says.

In addition, researchers will try to normalize results from inhibitor activity assays, which are used to test how well a drug candidate binds to and affects its target. They found in a previous study that their inhibitor compounds exhibit large potency differences based on their chemical properties simply as a result of minor changes in how activity assays are performed. 

“Our structurally diverse compound inhibitors allow for a maximally comprehensive analysis of these effects, as they can be made with a variety of chemical structures,” Heppner says.

The research will also involve a cutting-edge pharmacology approach: proteolysis targeting chimera (PROTAC). Instead of simply inhibiting a target proteins’ activity, PROTACs are compounds that degrade the protein altogether. 

The team’s inhibitor compounds use PROTAC technology to degrade kinases.

“PROTACs promote the destruction of the targeted protein into bits within the cell,” Heppner explains. “Using degradation as a tool to try to see what is happening inside the cell is faster than setting up an enzymatic drug discovery screen.”