Protein discovery could lead to less toxic cancer drugs
Thursday November 24th 2022
Better, less toxic cancer drugs could be developed following the discovery into how a key protein involved in a wide range of cellular processes works, British scientists have reported.
Scientists at The Institute of Cancer Research, London, have identified how the tankyrase protein switches itself on and off by self-assembling into 3D chain-like structures.
Writing in the latest edition of Nature, they say their findings will open the door to new types of cancer treatment that can control tankyrase more precisely than is currently possible.
It could also have implications for treating diabetes and inflammatory, cardiac and neurodegenerative diseases.
Tankyrase is an important protein that supports Wnt signalling, which are essential for the body to maintain stem cells and carry out processes such as cell division and development. The protein also controls other cell functions critical to cancer, such as the maintenance of the ends of chromosomes, the telomeres.
In this study, scientists draw parallels between the activation mechanism of PARP1 and tankyrase for the first time, suggesting that, similarly to PARP1, tankyrase works by being recruited to a specific site and self-assembling, clustering and changing its 3D structure to activate itself and perform its function.
Using cutting-edge cryo-electron microscopy, which freezes samples at -180°C to enable minute details of protein shape to be imaged, the team could visualise and capture how tankyrase self-assembles into fibres and why fibre formation is needed for tankyrase to activate itself.
They believe the domains – specific regions of the protein associating with different functions – that allow tankyrase to assemble and disassemble into different structures are exciting targets for future cancer drugs. They also believe that, depending on which structural domains drugs bind to, not all tankyrase inhibitors will affect Wnt signalling in the same way.
Study leader Professor Sebastian Guettler, deputy head of the Division of Structural Biology at The ICR, said: “Our study has provided vital new information about a particular protein molecule called tankyrase, which plays an important role in bowel cancer and other diseases but has so far eluded our understanding. We’re playing catch up – we have all these drugs to block tankyrase being created, but we don’t have enough basic understanding to use them as treatments.
“We have shown how tankyrase is switched on and can go from a ‘lazy’ enzyme to an active one. If we can create better, less toxic drugs to control this process, we could pave the way for an effective bowel cancer treatment in the future.”
Professor Kristian Helin, chief executive of The Institute of Cancer Research, London, added: “These fundamental findings help us understand how the extremely important tankyrase protein works within cells. Almost all bowel cancers have hyperactive Wnt-signalling that operates through tankyrase, and they could therefore potentially be treated with drugs targeting it.
“I am hopeful these key advances in our understanding of tankyrase will help us overcome the limitations of currently available drug candidates – hopefully bringing us a step closer to a new targeted bowel cancer treatment. Tankyrase is also responsible for regulating a wide range of processes relevant to a variety of diseases, not just cancer, so this research could have broad implications.”
Nature 23 November 2022
Tags: Brain & Neurology | Cancer | Diabetes | Heart Health | Pharmaceuticals | UK News
Printer
friendly page