Researchers at the Babraham Institute have used their understanding of cellular signalling to highlight a pitfall in an emerging treatment for cancer and inflammation. A new review just published in Biochemical Society Transactions summarises the researchers’ current knowledge, which includes details of their research published in Nature Communications earlier this year. Developing awareness around these findings will prevent wasted effort and resource being spent on further drug discovery research relating to this drug target by commercial pharmaceutical companies.
The research study focused on an emerging drug target in cancer and inflammation, and the use of small-molecule inhibitors to develop a new precision medicine – one that is matched to patients based on a genetic understanding of their disease. In this case, the compounds being investigated targeted a protein involved in cell signalling called ERK5. ERK5 is known to play an important role in some diseases, most notably in inflammation and cancer, and is thought to promote cell proliferation. Inhibiting this protein is an attractive strategy to develop novel anti-inflammatory or anti-cancer therapeutics and various large pharma have commercial research programmes to explore this for therapeutic purposes (for example, Bayer AG, Boehringer Ingelheim and AstraZeneca).
While conducting research using some potential ERK5 inhibitors, the research team of Drs Pamela Lochhead and Simon Cook at the Babraham Institute along with collaborators at Newcastle University, University of York in the UK, and Harvard Medical School in the USA, noticed an unusual effect; the inhibitors acted in the opposite way to what was expected and activated ERK5 instead of blocking it. The team applied their knowledge of the ERK5 signalling pathway to dissect the molecular basis of this.
As summarised in their latest review, the team found that the unintended activation of ERK5 was due to the binding location of the inhibitors. ERK5 inhibitors that bound to the kinase domain of the protein led to the protein being shuttled to the cell nucleus and activated.
Blocking ERK5 has therapeutic potential, but activating it could have undesirable consequences in terms of stimulated unwanted cell growth. Similar observations have been seen before with a precision medicine developed to treat melanoma (a form of skin cancer) where it unintentionally caused another type of skin cancer, cutaneous squamous-cell carcinoma.
These research findings and improved understanding will prevent this situation being repeated. Dr Pamela Lochhead, a senior postdoctoral researcher in the Cook lab and first author on the research paper and the review, said “It was surprising that the inhibitors we tested caused activation of ERK5, but we knew that by working out how this happened, we would be able to inform drug discovery efforts in developing new, safer medicines”.
Lochhead P., et al. Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors. Nature Communications, 2020 Mar 13;11(1):1383. DOI: 10.1038/s41467-020-15031-3
Cook, S. J., Tucker, J.A. & Lochhead, P. Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for… Biochemical Society Transactions
Dr Louisa Wood, Communications Manager, Babraham Institute, firstname.lastname@example.org
A detour sign (Shutterstock 1662418396).
Affiliated authors (in author order):
Pamela Lochhead, senior postdoctoral researcher, Cook labDavid Oxley, Head of the Mass Spectrometry facility
Andrew Kidger, postdoc researcher in the Cook lab
Victoria Johnson, former summer student in the Cook lab
Megan Cassidy, PhD student, Cook labSimon Cook, Head of Signalling research programme
This study was funded by a BBSRC project grant, an MRC-DPFS award and Institute Strategic Programme Grants from the BBSRC.
About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
14 September 2020