Answers are often elusive in the fight against cancer, and Rice University chemist Zachary Ball is hoping to pin one down — with pins made of single atoms. The work, which aims to create a drug that’s effective against an “undruggable” protein, is one of the first 50 proposals funded under the National Cancer Institute’s (NCI) Provocative Questions Project.
The Provocative Questions Project, in its inaugural year, is designed to spur innovative approaches to critical questions that could, if answered, substantially change the way scientists approach cancer research. Ball, assistant professor of chemistry at Rice, and collaborators at Baylor College of Medicine (BCM) are attempting to answer one of 24 questions posed by NCI: “Are there new technologies to inhibit traditionally ‘undruggable’ target molecules, such as transcription factors, that are required for (cancer)?”
“Most drugs are small molecules that bind tightly to a protein and literally get in the way of it sticking to whatever it might normally interact with, often another protein,” Ball said. “Drugs tend to be small molecules because those are the easiest to introduce into cells and because small molecules are particularly effective at binding tightly into the tiny pockets that exist on many proteins.”
Unfortunately, there are some proteins that don’t have the tiny pockets favored by drug designers. By some estimates, small-molecule drugs are ineffective against as many as 80 percent of the proteins in human cells, including many signaling proteins and a class of proteins called transcription factors that help control basic functions like cell death and cell reproduction. Drugmakers often call these proteins “undruggable.”
“Researchers have actually spent a good deal of time and effort looking for drug candidates that are effective against some of these undruggable targets,” Ball said. “But the results are generally mediocre, and affinity is a big reason why. Without a classical binding pocket, we tend to see inefficient binding with relatively flat protein surfaces that are not designed to bind drug-like molecules. Our idea is to add well-placed rhodium atoms that will act like pins to hold an otherwise mediocre drug candidate in place.”
The NCI project grew out of a collaboration with Michele Redell, assistant professor of internal medicine at BCM, and David Tweardy, professor of medicine and chief of the section of infectious diseases at BCM. Ball, Redell and Tweardy won seed funding in January from the Simmons Family Foundation for a project aimed at developing new drugs to treat acute myeloid leukemia (AML), which afflicts thousands of new patients every year, many of them children.
In particular, the group was interested in modifying a drug candidate compound to improve its effectiveness against STAT3, a transcription regulating protein that has been implicated in AML and numerous other cancers, including gastric, renal, breast, ovarian, skin and brain cancer. STAT3 is an especially compelling area of study because previous research has shown that targeting STAT3 may allow for effective treatment of “multiple drug-resistant” tumors for which available treatments are ineffective.
“The Simmons grant allowed us to gather preliminary evidence to bolster our case for creating a hybrid drug that combines the benefits of both traditional drugs and metal-based drugs,” Ball said. “The prior work really strengthened our proposal, and we’re hoping to use the two-year ‘Provocative Questions’ grant to lay the scientific foundations for future translational studies.”