Jack Taunton is a trained chemist who independently studied cell biology so he could explore the fascinatingly complex work performed by cellular proteins. Today, he creates novel and useful molecules and watches them interact with cellular proteins to reveal human disease processes. The potential payoff: a new class of targets—and methods for hitting them—in cancer and other intractable diseases.
Taunton, a professor at the University of California, San Francisco, says his career path was set early by two projects he took on as a graduate student at Harvard University, where his adviser was HHMI investigator Stuart Schreiber. Learning to synthesize molecules found in nature, while having what he recalls as "no understanding of biology," Taunton focused on a complex antibiotic compound and got close enough to synthesizing it to publish a paper with his results. But he chose not to pursue it further. Instead, he took a "dramatic career turn" and started working on problems he found more interesting biologically. He wanted to go beyond making compounds and actually understand how they function.
He began to learn biology by reading the Journal of Cell Biology, Cell, and other journals. "I didn't take classes in biology, but I was surrounded by very talented biologists who taught me everything I know," Taunton says. He chose for his next project a relatively simple compound he came across in a journal article. The compound, trapoxin, was not particularly challenging for a chemist to synthesize, he says, but it was biologically fascinating and had an unusual, chemically reactive substructure. "Trapoxin influenced cancer cells to change shape and look more like normal cells—and they stopped dividing," he explains. "I was fascinated by the possibility that such a chemically reactive substance could have such specific effects on cells."
He synthesized trapoxin and elucidated its protein target, an enzyme that had been widely sought but never purified or cloned. Using techniques from chemical synthesis, biochemistry, and cell biology, Taunton purified the enzyme, called histone deacetylase, and cloned the human gene that encodes it, revealing its identity as a regulator of gene expression.
That discovery convinced Taunton that even chemically reactive molecules can interact specifically with protein targets in living cells to reveal cellular processes. He began to think that he could create his own cache of small molecules to be used as tools to explore the inner workings of the cell. That revelation underlies several of the projects in his lab today.
Recent targets for Taunton's small molecules have been protein kinases, which regulate nearly all cellular processes and therefore have become important tools for the study and treatment of many human diseases, including heart disease, cancer, and several parasitic diseases. The real challenge, however, is that there are 500 or so kinases encoded by the human genome, and all are remarkably similar. "Distinguishing one kinase from the other 500 with a small molecule is very challenging in terms of molecular recognition," he says.
Taunton has taken on the challenge, devising a system for designing and synthesizing ultraspecific, irreversible kinase inhibitors. His inhibitors exploit two "filters" that are specific to a single kinase and no others—the small molecule's shape has to fit precisely the kinase's active site, and it must react chemically with a single amino acid, called cysteine, that is specific to that kinase's active site.
He proved the utility of his approach in 2005 with an inhibitor of the kinase p90 RSK, which enabled Taunton's team to decipher RSK's signaling pathway in cells and to show that inhibiting it may have therapeutic benefit for heart disease and cancers.
How does Taunton choose which of the 500 human kinases to target? "It's really important for me to go after kinases that we don't know that much about," he says. "I choose kinases for which we have no known inhibitors."
Taunton follows the same philosophy in choosing to go after kinases in the parasites that cause diseases such as Chagas disease and African sleeping sickness. "For parasitic diseases, the problem is even more extreme," he says. "Not only do we not have useful inhibitors, we don't even know which kinases to go after yet." For that challenge, he turns the tables and aims for multispecificity, or what he calls semipromiscuity, to narrow the search for the relevant kinases.
"It's too hard," he says, to go after all 156 kinases in Trypanosoma brucei, for example, the parasite that causes African sleeping sickness. His semipromiscuous probes help him narrow the field and speed that search; then he can devise an inhibitor specific to the kinases that he finds are most important to the parasite. Already his team has invented a new kinase inhibitor that potently kills T. brucei.
Taunton is planning to branch out beyond kinases, ultimately to enzymes that traditionally have been difficult to target with small molecules. He has his eye on protein-protein interactions as well. But he'll continue to aim for uncharted waters. "Part of the success I've had has been choosing problems that others aren't working on," he says.