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PHD graduate Chloe Gerak targets protein-protein interactions in cancer

February 5, 2020

Chloe Gerak took aim at the uncontrolled cell division in cancer using a combination of high throughput screening, computational modeling, and NMR to find and characterize small molecule inhibitors of protein-protein interactions. In a study published in the Journal of Biological Chemistry her focus is on a member of the ETS family, ETV6, which plays an important role in embryonic development and hematopoietic regulation. Structurally, ETV6 has two protein domains: an ETS DNA-binding domain and a PNT domain. The PNT domain of ETV6 is of particular interest to Gerak, as it’s able to self-polymerize, allowing for multiple PNT domains to come together, which then allows the ETS DNA-binding domain to bind to DNA with higher affinity.

The ETV6 PNT domain has been found in numerous chromosomal translocations, which have been found in over 40 different types of cancer. The cancer-causing mechanism is thought to be related to the PNT domain’s self-polymerization property, as this brings the fusion proteins produced from the translocations together. If the fusion is to a receptor tyrosine kinase, this results in their dimerization, which is the mechanism that activates their kinase activity. This in turn stimulates downstream signaling pathways, often resulting in uncontrollable cell division and cancer. This makes the PNT domain a great target for a chemotherapy drug.

In her search for a molecule that will inhibit PNT domain polymerization, Gerak, a PhD candidate in the Department of Biochemistry and Molecular Biology at the Life Sciences Institute designed a high throughput split luciferase screening assay to do just that. After screening more than 17,000 compounds for a reduction in light (and therefore an inhibition in dimerization), she got a few hits, but they also resulted in the same decrease in emission in the control cell line. She screened an additional library that specifically targets protein-protein interactions. Working with a collaborator in Bristol, used molecular modelling in their BUDE (Bristol University Docking Engine virtual screening platform to screen 8.2 million compounds that were each in 20 different conformations to either interface of the PNT domains, and ranked the top thousand hits. The findings from these screens were published in SLAS Discovery.

Chloe Gerak completed a PhD  in the Department of Biochemistry and Molecular Biology at the Life Sciences Institute. She was co-supervised by Dr. Lawrence McIntosh and Dr. Michel Roberge.  Dr. Gerak is now a postdoctoral fellow at the University of Melbourne in Australia. While finishing her doctorate, she sat down with Science in the City to discuss her research and the challenges she has faced throughout her time as a scientist. 

Story reported by Science in the City February 4, 2020

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