(Toronto – June 29, 2010) The Samuel Lunenfeld Research Institute’s Drs. Frank Sicheri and Mike Tyers, in collaboration with researchers at the University of Edinburgh and McMaster University, have discovered a previously unknown small molecule that inhibits a key enzyme involved in several important cellular processes.
The discovery will provide researchers with a greater understanding of human biology, and may also lead to the development of newer, more sophisticated drugs to treat cancer and other illnesses.
The study was published in the June 27 issue of Nature Biotechnology.
By studying the common baker’s yeast Saccharomyces cerevisiae, the researchers found that the small molecule, called SCF-I2, selectively inhibits Cdc4, a member of a large class of enzymes (large proteins) known as ubiquitin ligases. Ubiquitin ligases ‘tag’ proteins for destruction, and therefore are a promising target for therapeutic intervention.
SCF-I2 is the first molecule of its kind to be discovered, and has a highly selective effect on a region of Cdc4 called the WD40 domain, which is found in hundreds of other human proteins. The human counterpart of Cdc4 (known as Fbw7) behaves similarly to the yeast protein, so SCF12 may therefore be adapted for the development of newer, more ‘intelligent’ drugs to treat illnesses including cancer.
“It appears that SCF-I2 takes advantage of the way the WD40 domain is structurally hard-wired,” said Dr. Sicheri, a Senior Investigator at the Lunenfeld renowned for his research in cancer biology, and specifically for his expertise in uncovering the structure of proteins. “We were surprised to learn this, and what we found could give us insight into the entire class of similarly structured proteins that contain similar WD40 domains.”
By using sophisticated x-ray techniques to visualize a protein’s structure and high- throughput robotics to find SCF-I2 within a large library of 50,000 drug-like compounds, Drs. Sicheri and Tyers and their team found that SCF-I2 inhibits the ability of Cdc4 to interact with its protein targets.
“Cdc4 and its related family members control the levels of many important proteins, and therefore hold untapped potential for drug discovery,” said Dr. Sicheri.
Dr. Sicheri noted that SCF-I2 can potentially be used to develop anti-fungal agents (often important in treating immunocompromised patients), for the development of anti-cancer medications, and for the reprogramming of human stem cells.
This study was supported by the Canadian Institutes of Health Research, the Ontario Research and Development Challenge Fund, the National Cancer Institute of Canada, and the European Research Council.