Enzyme research could advance anti-cancer drug development

In a breakthrough that could revolutionize the development and design of anti-cancer drugs and drugs to treat other diseases, researchers at the UW Medical School have identified the molecular basis through which a family of enzymes involved in several life-threatening diseases — including cancer, diabetes, heart disease and stroke — communicates information to cells.

Richard Anderson, a professor in the Department of Pharmacology, and postdoctoral fellow Jeannette Kunz have discovered how a family of 13 closely related enzymes produces “second messengers,” molecules that regulate many functions throughout the body. These second messenger molecules carry instructions to cells, signaling them to grow, move about, communicate with other cells and respond to threats to the body’s immune system.

What had baffled researchers for years was the question of how this particular family of enzymes, each of which has a similar chemical structure and appearance, could produce wildly different secondary signaling messengers.

Kunz and Anderson’s research has pinpointed the answer: an activation loop composed of a short sequence of amino acids is the agent responsible for determining which secondary messengers are produced by each enzyme. Armed with this knowledge, pharmacologists will now be able to begin designing drugs that can either block the enzymes from creating the signalling messengers or stimulate them to create more.

Anderson likens this signaling process to an electrical system in a house, with a series of “switches” that create physical effects. By understanding how the enzymes work to create secondary messengers, researchers now understand how to flip the “on” and “off” switches, controlling the level of messengers and, by extension, the flow of biochemical information.

“This discovery has several critical implications, but the most important part is that we can now begin to design drugs that will block these enzymes from stimulating the messengers that participate in, for example, cancer and cancer metastasis,” says Anderson. Blocking the enzymes could also modulate cell processes in other disease states, including diabetes, heart disease and stroke.

The effects of Kunz and Anderson’s work aren’t expected to be limited to disease therapies. This same family of enzymes also creates messenger molecules that are critical in basic physical functions such as the contraction of the heart and secretion of insulin. Using this information, pharmacologists should also be able to design drugs that flip the enzymes’ switch “on,” allowing the signalling messengers to increase an individual’s heart rate or production of insulin.

“This is a foundation for an entirely new set of work,” said Anderson. “Will this lead to a drug that will effectively treat cancers? Not tomorrow, but perhaps in future years.”

Kunz’s paper, “The Activation Loop of Phosphatidylinositol Phosphate Kinases Determines Signalling Specificity,” appears in the January edition of Molecular Cell, a leading cell research magazine.