Team of CRINA researchers discovers potential new class of cancer drugs

Compounds that inhibit a particular DNA repair activity could permit lower doses of cancer treatments and reverse drug resistance.

Adrianna MacPherson - 06 November 2019

A team of University of Alberta researchers have discovered a group of novel compounds that have the potential to significantly impact patients receiving cancer treatment. The team includes Cancer Research Institute of Northern Alberta (CRINA) members Frederick West (Co-director of CRINA), Michael Weinfeld, Jack Tuszynski and Khaled Barakat. Their article "Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF" was published in the high impact scientific journal Journal of Medicinal Chemistry.

Why are these compounds needed?

Many widely used cancer treatments, such as radiation therapy and some chemotherapy drugs, work by damaging the DNA of cancer cells. The cancer cells are then unable to continue growing and eventually die.

However, in certain situations, DNA repair systems can go into overdrive and allow cancer cells to survive and become resistant to treatment. Researchers are interested in finding ways to inhibit DNA repair so that resistant cancer cells would once again be vulnerable to treatment. The multidisciplinary team based out of the University of Alberta looked at a particular protein duo, ERCC1-XPF, which had not yet been extensively studied. These two proteins are able to repair DNA damage only when they are associated with each other. By interfering with this association using a third molecule, the undesired resistance due to increased DNA repair activity could be prevented.

How is a drug for cancer treatment created?

Though patients only see the end result, there is far more that goes into creating a cancer drug than many may think. This particular project was initially funded by a $2.9 million grant from the Alberta Cancer Foundation, and started several years ago. A team of diverse scientists, from computational biophysicists to chemists to pharmacologists, formed a group that had a goal of creating compounds designed to make cancer cells more sensitive and receptive to current treatments. The team was able to use their diverse areas of expertise and resources to push the discovery forward through collaboration.

The range of resources used in the process was vast. The team started by employing a sophisticated computer software program to screen chemical compounds that would interfere with ERCC1-XPF binding. Certain compounds had promising elements that often appear in successful drugs, as they determine things like how easily and quickly the compound is absorbed and metabolized by a patient.

Examining the initially identified active compounds, the chemists on the team examined ways in which they could change the structures to improve their properties. The computational scientists then looked at the impact that these changes would have at a molecular level and tried to predict what issues they might cause.

Eventually, the group collaboratively identified several compounds that could potentially stop the ERCC1 and XPF proteins from interacting. The chemists synthesized the compounds which were then tested to verify that they did, in fact, inhibit ERCC1 and XPF from binding to each other. One particular compound was identified as the most optimal inhibitor, and it was selected as the lead candidate for further optimization as the team's work progresses.

The research team has already filed a provisional patent application, and are looking to further refine the structure of the lead compound. While future compounds generated have the potential to impact a variety of cancers, potential targets include lung cancer and colorectal cancer. The team has a goal of beginning preclinical animal studies in 2020.