Uncovering world’s first structural clues to inhibiting an emerging DNA Damage Response target area for future anti-cancer therapy

Collaborative team from AstraZeneca, University of Sheffield and Pelago BioSciences publish the co-crystal structure of flap endonuclease 1 (FEN1) bound with small molecule inhibitors in Nature Chemical Biology and describe how its function can be inhibited to provide clues for future drug discovery.

Through an exciting collaboration with our scientists in the Innovative Medicines & Early Development Biotech Unit (IMED), the University of Sheffield and Pellago BioSciences, we have shown for the first time how small molecule inhibitors bind to flap endonuclease 1 (FEN1), an emerging drug target in the DNA Damage Response (DDR).

The ability of our DNA to retain its double-stranded helical structure is key to maintaining its stability and functionality. FEN1 is an enzyme that removes unwanted ends of single stranded DNA formed during every day DNA replication and repair. Removal of these protruding ends allows the helical structure of the DNA to reform and maintain its stability. The enzyme forms part of a network of cellular pathways that minimise the daily impact of DNA damage known as the DDR.

Higher levels of FEN1 have been seen in cancer types associated with poor prognosis, potentially as a result of these cancer cells being reliant on this repair enzyme in the absence of other supporting DDR proteins. This over reliance on FEN1 repair means the cells become sensitive and die when FEN1 is blocked – a term called synthetic lethality. Preventing the action of enzymes like FEN1 may be a way of selectively killing such cancer cells as a new therapeutic class of anti-cancer agents.

The joint team used crystallography, binding kinetics and cellular assays to show for the first time how small molecule inhibitors bind to FEN1. Their findings are published in August 2016 issue of Nature Chemical Biology. Detailed images of the way the inhibitors bind and block FEN1 provide clues as to how the functionality of the protein can be prevented and was complemented by detailed studies of the effects of inhibition of FEN1 on cell function within the DDR.

“Uncovering how a specific set of FEN1 inhibitors block the functionality of this DDR enzyme provides valuable insight to help us develop future anti-cancer therapies. We are very fortunate to have worked with Jane Grasby’s group at the University of Sheffield who have worked on understanding the secrets of FEN1’s role in human DNA replication and repair for many years. Pelago Biosciences provided valuable data supporting the inhibitors bind to FEN1 in cells. This has been a great example of how multiple collaborations help further our research understanding of this important area in oncology.” said Dr Stephen Durant, Bioscience Lead, IMED Biotech Unit.

“Sharing our corporate expertise in assay development and structural chemistry with Jane’s group has worked very well in this setting, and we have gained a better understanding of the target from Jane’s work as a result” added Dr Willem Nissink, Medicinal Chemistry Lead, IMED Biotech Unit.

DDR is one of AstraZeneca’s key strategic areas of focus in Oncology drug discovery and development. As illustrated by this early scientific research we are committed to understanding the functionality and importance of potential DDR targets to allow us to exploit the cancer cell’s reliance on remaining DDR pathways. Targeting DDR deficiencies to preferentially kill cancer cells, while minimising the impact on normal cells, has the potential to provide a new way to treat cancer.

NOTES FOR EDITORS
 

About Sheffield University
With almost 27,000 of the brightest students from over 140 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world’s leading universities.

A member of the UK’s prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines. Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in.

About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.

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