Toronto, ON – The Samuel Lunenfeld Research Institute’s Drs Derek Ceccarelli and Frank Sicheri, in collaboration with colleagues at Mount Sinai Hospital, Celgene Corporation, the Université de Montréal and the University of Edinburgh, have discovered how a small molecule selectively inhibits a key enzyme involved in the regulation of key cellular growth processes. The discovery provides researchers with a greater understanding of cellular control processes, and may also lead to the development of newer, more sophisticated designer drugs to treat cancer and other illnesses.
The study is available online today and will be published in the July 15 issue of the leading biomedical journal Cell.
The researchers found that the small molecule, termed CC0651, selectively inhibits Cdc34, a member of a class of enzymes known as ubiquitin-conjugating enzymes, or E2s. These are important targets for drug discovery as they ‘tag’ other proteins for destruction by attaching chains of ubiquitin proteins, and are beginning to yield an exciting new class of therapeutic targets.
Using sophisticated x-ray imaging techniques to visualize Cdc34’s three-dimensional structure and how it binds to the inhibitor, Dr Ceccarelli, a research associate at the Lunenfeld and first author of the study, identified how CC0651 specifically recognizes Cdc34, but not other E2 enzymes found within cells.
“If we inhibit Cdc34, then one would expect to see increased levels of the proteins that are normally tagged for destruction by this E2 in a cell,” he said.
One of the targets of Cdc34 is p27, a protein that normally acts as a brake to prevent cells from dividing. Decreased levels of p27 indicate poor prognosis in many cancers since tumour cells that lack p27 will continue to divide. The researchers demonstrated that treatment of certain cancer cell lines with CC0651 or related compounds increased levels of p27 and reduced cell proliferation. Further studies are aimed at determining other targets of Cdc34 that become stabilized following CC0651 treatment.
“Cdc34 and other members of the E2 family of enzymes control the levels of many important proteins in addition to p27-which are also important in controlling cell proliferation and other cellular processes-and therefore hold new, untapped potential for drug discovery,” said Dr Sicheri, senior investigator at the Lunenfeld and the senior study author.
CC0651 represents the first example of a small molecule that targets an E2 conjugating enzyme. Chemists at Celgene Corporation initially identified CC0651 from a large library of compounds and provided all of the inhibitor required for follow-up experiments.
“This is an excellent example of a synergistic collaboration between a pharmaceutical company and a team of academic scientists,” noted Dr Jim Woodgett, director of research at the Lunenfeld. “By leveraging the ability of several key experts, partnerships of this nature can provide new opportunities to discover and accelerate the development of promising drug candidates.”
The study was supported by the Canadian Institutes of Health Research.