The National Institutes of Health recently awarded Associate Professor of Chemistry Justin Miller a three-year, $355,000 grant through the National Cancer Institute for a project designing anticancer molecules.
The major goal of Miller’s project is the synthesis of a host of potential anticancer chemotherapeutics structurally similar to natural products that inhibit a protein partly responsible for carcinogenesis.
“Cancer cells generally lack certain molecular machinery that would cause them to destroy themselves,” Miller says. “That machinery is partially restored by inhibiting proteins collectively called histone deacetylases (HDACs).”
DNA spends most of its time in a cell wrapped around proteins called histones, and must be uncoiled to be used.
“Drugs that inhibit HDACs keep histones from sticking to DNA, thus allowing DNA to uncoil and generate anticancer proteins,” Miller says. These anticancer proteins are the cellular machinery that help cancerous cells recognize that they are not functioning correctly and alerts them to self-destruct.
But for cells that have lost that ability, “you want to have drugs that bind specifically to one type of HDAC,” Miller says. “The more specific the drug, the better it may work, which is why we need to make analogs.”
Analogs are molecules, synthesized from scratch, that are chemically similar but not identical to natural products (molecules found in nature).
“Synthetic analogs can be synthesized by the same procedures used to make their natural counterparts,” Miller says, “but only if the synthetic route is flexible. We’ve completed a total synthesis of a potential anticancer chemotherapeutic natural product, and we’re now working on another. Both have been synthesized by other groups, but our synthetic route is different. It’s more amenable to making analogs.”
This grant is an Academic Research Enhancement Award, which Miller says “is designed for faculty at primarily undergraduate institutions like HWS to work on big research questions.” This NIH grant will give students the chance to explore the practical applications of reactions they have learned-or will soon learn-in class.
Deirdre Wholly ’11, Wade Perkins ’12, Ariella Korn ’12, Xiaoyu Zang ’13 and Heli Shah ’13 are all working with Miller to build these natural products and analogs in a way significantly different from any other currently established method, which holds the promise of generating possible drug candidates that other methods have not been able to generate. This August, Miller and four student collaborators will travel to Boston to present this summer’s findings at the national conference of the American Chemical Society.
“It’s rare to find chemistry done alone; it’s almost always a collaborative effort,” says Miller. “Grants give faculty the opportunity to work with students, which helps students learn and helps research move forward. That’s the key. That’s the fun part.”