Yale Scientist Will Target Cancer Protein to Cell's "Recycling System"

Tim Corson

Tim Corson, a Yale postdoctoral fellow in the Department of Molecular, Cellular & Developmental Biology, received two top fellowship honors from the Canadian Institutes of Health Research (CIHR) in Ottawa on November 20 for his proposal of a research project to target and destroy a protein commonly active in cancer.

Corson received the Jean-François St-Denis Fellowship in Cancer Research for the top-ranked proposal in the field of cancer research in the 2006-2007 competition, and a Bisby Fellowship for submitting the overall top-ranked post-Ph.D. proposal in February 2007 competitions.

“One of the most common features of cancer cells is excessive activation of a protein called Ras that acts as a molecular switch,” said Corson. “In its active form Ras stimulates cells to grow, while in its inactive form, Ras does not have this effect. We are targeting the active form of Ras for destruction as a powerful way to turn off the growth of cancer cells.”

Corson is engineering a way to target specifically the active Ras cancer protein for destruction. He will use PROTACS, or PROteolysis TArgeting Chimeric moleculeS, a technique developed in the laboratory of his mentor, Professor Craig Crews of Yale, which permits the specific destruction of almost any protein by linking it to a molecule that directs it to the cell’s protein recycling system — ubiquitin-proteasome pathway — creating a signal for the protein to be digested by an enzyme complex known as the 26s proteasome.

“PROTACS acts as a chemical bridge between the targeted protein and another protein that marks the first for destruction by the cell’s recycling mechanism,” said Corson.

Corson will use PROTACS to recognize and attack the active Ras protein using a small molecule called nadazole, which he designed in collaboration with Professor Bill Jorgensen in the Chemistry Department. He also proposes to develop a way to rapidly screen many thousands of chemicals for their ability to associate only with active Ras for further use with PROTACS targeting.

“This project will develop an important new tool for targeting a specific individual form of a protein,” said Crews. “Destroying activated Ras by PROTACS will be an exciting first step in developing drugs that have the same effect. Such Ras-targeting drugs would likely be effective against multiple cancer types.”

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Janet Rettig Emanuel: janet.emanuel@yale.edu, 203-432-2157