Issue Date: January 24, 2011
Ronald Breslow Award For Achievement In Biomimetic Chemistry
Kevan M. Shokat can’t get enough of kinases. After spending more than 15 years developing powerful chemical tools to probe the identity and function of dozens of these phosphate-transferring enzymes, the University of California, San Francisco, chemical biologist admits he doesn’t see a way out anytime soon. “There are still some 400 kinases left to go.”
Shokat, currently professor and chair of UC San Francisco’s department of cellular and molecular pharmacology as well as an investigator with the Howard Hughes Medical Institute, first caught the kinase bug as a postdoc in a Stanford University immunology lab. One of his benchmates was trying to identify a kinase that was seemingly tied up in a signaling pathway involved in the mouse immune system. “You could tell that a kinase was involved but not which one,” Shokat recalls. “All you could do was start knocking out kinases” in mice and seeing whether their immune system functioned as expected. As a newly minted Ph.D. chemist, “I was struck by how imprecise the available tools were.”
When he started his own lab at Princeton University soon after, Shokat set out to develop better tools for identifying kinases and their roles in cells.
Not long after, while playing with his young son, he hit upon a clever and general approach for directly identifying the substrates of protein kinases. The strategy relies on engineering kinases so that they accept an unnatural nucleotide cofactor capable of trapping the kinase’s substrate. It’s now found widespread use among those working with kinases.
Shokat, who left Princeton for UC San Francisco in 1999, went on to develop a complementary method for generating cell-permeable inhibitors of the same engineered kinases. Such inhibitors have allowed scientists to probe kinase function in living cells.
Shokat, 46, is “the leading biological chemist of his generation,” says Peter G. Schultz of Scripps Research Institute, with whom Shokat got his Ph.D. at UC Berkeley after undergraduate work at Reed College.
“His methods have been applied to a large number of signaling and regulating cascades in cell biology and across a wide expanse of biology and medicine,” Schultz explains. “His chemical approaches for studying kinase networks have become a gold standard” for investigating signaling networks, he adds.
Indeed, Shokat’s technology for constructing analog-sensitive kinases is now used by mouse genetics firm TaconicArtemis, which provides mouse models to pharmaceutical companies and academic laboratories.
He founded Intellikine in 2008 to explore the therapeutic potential of inhibitors of phosphoinositide-3-kinases. These kinases control the development of cancer, nutrient sensing, and responses to DNA damage. Shokat’s selective inhibitors for single members of this enzyme class “have a high likelihood of making a clinical impact in the near term,” Schultz says.
In recent years, Shokat’s lab has also developed chemical methods for studying the structure of chromatin, the cellular component in which DNA is wrapped around histone proteins. His team’s strategy for constructing histones containing lysines with one, two, or three methyl groups has helped address numerous questions about how patterns of these common amino acid modifications regulate chromatin structure.
Still, Shokat says, his heart remains with the kinases. “I can’t let them go.”
He will present the award address before the ACS Division of Biological Chemistry.
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