A New Frontier of Drug Discovery
Epigenetics is providing protein targets and chemical bullets to make powerful new cancer and inflammation-related drugs

June 1, 2015

In her office at the University of Toronto, Dr. Cheryl Arrowsmith opens a complex, colour image on her computer screen. The image could be post-modern art: interconnected blue lines, hinged at red circular joints set against a globular multicolored background. To Dr. Arrowsmith, a structural biologist, the image represents a new, largely unexplored frontier of drug development.

The colourful blob is a protein that controls whether specific genes are turned on or off. Dr. Arrowsmith refers to these as epigenetic proteins. The image also shows a new chemical probe her lab has developed, a molecule meticulously designed to fit snugly into the protein's structure.

Dr. Arrowsmith's lab is part of a collaborative network of researchers that are laying the groundwork for the development of epigenetic-targeted drugs, to treat diseases from cancer to inflammatory disorders.1

"There's so much evidence that epigenetic proteins are important in disease and could be potential drug targets that we think the best way to explore this is to create chemical probes and use them to explore as many disease models as possible," she says. In fact, she is so passionate about epigenetics, that her team is generating "Open Access" chemical probes – making them available for the world to test in disease models without licensing or restrictions on use.

Over the past decade, epigenetics – literally meaning "above" genetics– has emerged as a new frontier for understanding what makes cells tick – and sick.2 We know that every cell in the body contains exactly the same genes. But there are many different ki"ds of cells in the body. This raises a question: how can cells that all carry the same instructions develop different functions?

"It's the epigenetic proteins," explains Dr. Arrowsmith.

This collection of several hundred proteins acts to regulate which genes are active in a given cell during its development. This determines, for example, whether the cell matures into a liver cell producing digestive enzymes or a protective skin cell.

The growing awareness of epigenetics has sparked a flurry of medical interest because while genes can't readily be changed, epigenetic proteins can. Their action is reversible, making them excellent potential drug targets.

"Probes against epigenetic [proteins] are the next frontier in medicinal chemistry," says the University of British Columbia's Dr. Colby Zaph, one of Dr. Arrowsmith's Canadian Institutes of Health Research (CIHR)-funded collaborators.

Chemical Probes

Dr. Arrowsmith's research involves first using x-ray crystallography and Nuclear Magnetic Resonance (NMR) techniques to determine the precise 3D structure of an epigenetic protein. Team members then identify target areas in the protein where a small molecule might fit and tightly bond with the protein. Working with academic and pharmaceutical company chemists, the Arrowsmith group finds a small molecule, the chemical probe, that will efficiently and durably bind to the protein to slow or accelerate its action.

As of 2013, there were four epigenetic therapies approved for patients in the United States, all to treat cancers, and there are currently more than a dozen in U.S. clinical trials.3

"I think these are just the tip of the iceberg," says Dr. Arrowsmith.

However, pharmaceutical scientists say the bottleneck in developing these new drugs is identifying the small molecules – the chemical probes – that can alter an epigenetic protein's behaviour.4 This is exactly where Dr. Arrowsmith's lab is a world leader.

In a recent paper in the Proceedings of the National Academy of Sciences, Dr. Arrowsmith and colleagues at Pfizer described how they painstakingly identified the first chemical probe that can inhibit an epigenetic protein called SETD7.5 The protein plays an important role in regulating tissue size and growth, which are out-of-control in cancer tumours.

Dr. Arrowsmith's team, including more than a dozen collaborators, revealed that a probe named (R)-PFI-2 binds to the protein, inhibiting its function. They also showed that the probe can readily enter cells, a critical feature for any potential drug.

"Researchers interested in understanding epigenetic regulation and pharmaceutical companies interested in SETD7 as a drug target will jump on this work," says Dr. Stephen Burley, Director of the Protein Data Bank, based at Rutgers University in New Jersey.

The research was done as part of the Structural Genomics Consortium (SGC), a unique academic-industry collaboration of university and pharmaceutical company researchers based on Open Access principles. In this partnership, the SGC identifies 3D protein structures and industry helps develop the drug-like chemical probes – all of which are made fully available to the wider biomedical research community in order to accelerate the pace of discovery.

The Structural Genomics Consortium (SGC)

The SGC is a not-for-profit, public-private partnership that supports the discovery of new medicines by identifying the 3D structures of medically-relevant proteins. With more than 200 scientists centered at labs in Toronto, Canada, and Oxford, England, it's the world's leading source of new protein structure information. These proteins are important to the development of new therapies for cancer, diabetes, obesity, and inflammatory and psychiatric disorders. The SGC is funded by nine pharmaceutical companies, and public partners including CIHR. All of the SGC's outputs – including chemical probes – are made publically available without restrictions on use.

"The companies give us libraries of thousands of drug-like molecules that we can use in our assays to identify the few that inhibit a given protein," says Dr. Arrowsmith, the scientific lead for the Toronto section of the SGC. Experienced chemists in industry then work to optimize the promising molecules based on how the chemicals fit into the 3D proteins structures. "Through this collaboration we've developed 27 chemical probes that are now available for the community to use."

Evidence in Action: Toward new drugs for IBD

Dr. Arrowsmith's current CIHR-funded research projects are demonstrating the potential power of epigenetic drugs in creating new treatments for Inflammatory Bowel Disease (IBD) and cancers, diseases known to involve a high level of epigenetic deregulation.

In a recently published study, Dr. Zaph demonstrated that a chemical probe developed in Dr. Arrowsmith's lab blocks the activity of an epigenetic protein thereby inhibiting immune cells' ability to spark inflammation.6

"The probe allowed us to tease apart the intricate mechanisms of how the epigenetic protein regulates gene expression and cellular differentiation" says Dr. Zaph, noting that the protein is also active in human immune cells.

Dr. Arrowsmith says the pace of discovery as a cornerstone lab in the SGC is at times daunting.

"We have to solve a specific number of structures every quarter, and our goal is to develop about ten new chemical probes each year," she says. But knowing that each intriguing 3D image on her computer screen is the potential building block for a potential new therapy is powerful motivation.

"It's really exciting," says Dr. Arrowsmith. "I feel like we're not only doing our own research, we're catalyzing other peoples' research and drug discovery as well."


Footnote 1

Burridge, S., "Target watch: Drugging the epigenome," Nature Reviews: Drug Discovery, 12 (2013):92-93. doi:10.1038/nrd3943.


Footnote 2

Arrowsmith, C., et al. "Epigenetic protein families: a new frontier for drug discovery," Nature Reviews: Drug Discovery, 11 (2012):384-400. doi:10.1038/nrd3674.


Footnote 3

DeWaskin, V.A., and Million, R.P., "The epigenetics pipeline," Nature Reviews: Drug Discovery, 12 (2013):661-662. doi:10.1038/nrd4091.


Footnote 4

Campbell, R., and Tummino, P., "Cancer epigenetics drug discovery and development: the challenge of hitting the mark," The Journal of Clinical Investigation, 124,1 (2014):64-69. doi: 10.1172/JCI71605.


Footnote 5

Baryste-Lovejoy, D., et al. "(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells," Proceedings of the National Academy of Sciences, 111,35 (2014):12853-12858. doi: 10.1073/pnas.1407358111.


Footnote 6

Antignano, F., et al. "Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation," The Journal of Clinical Investigation, 124,5 (2014):1945-1955. doi:10.1172/JCI69592.


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