Scientists at the University of Dundee have developed a new technology that provides a greater understanding into the biology of ‘undruggable’ diseases.
Cells are composed of thousands of interacting proteins and their malfunction is a primary mechanism of disease development. Drug discovery scientists’ goal is to identify these aberrant proteins, understand their function and develop novel compounds to target them.
Conventional methods used to understand these proteins are very costly and have limitations that prevent researchers to control protein levels directly, quickly, and reliably.
Dundee’s ‘BromoTag’ system allows scientists to determine which individual proteins possess the greatest potential as targets for new therapeutic agents. Using genome-editing technologies, BromoTag pins a small biological tag to a target protein and labels it for degradation, allowing researchers to evaluate its functional role and impact on disease development.
Targeted protein degradation co-opts the cell’s natural disposal systems to remove target proteins and is increasingly applied as a tool to study biology as well as to develop medicines for diverse therapeutic areas including oncology, inflammation, dermatology, immunology, and respiratory diseases.
BromoTag was developed the University’s Centre for Targeted Protein Degradation (CeTPD) in collaboration with researchers from Dundee’s MRC Protein Phosphorylation and Ubiquitylation Unit. The close interaction of the fields of chemistry and biology was critical to this success, as it allowed researchers to optimise both the small chemical molecule and the biological tag.
Conner Craigon, a PhD student at CeTPD who led the biology component of the research, said, “Our findings provide a new chemical genetic tool to enable scientists to promote rapid and selective removal of any individual protein, for example proteins which are either understudied or difficult to investigate using current biological tools. The new system has been shown to be adaptable and can be applied to many different proteins.”
The chemistry research was headed up by Adam Bond, another PhD student at CeTPD, who said, “BromoTag, while still in its first development, has shown to be a powerful tool to probe biology. We wanted to develop a small-molecule able to degrade the tagged protein potently, in other words at low concentration, within minutes and reversibly, and critically to degrade only that individual target protein and prevent any off-target effects.
“The primary beneficiaries of our work are academic scientists, who can apply our system to better understand how their target proteins function, and industrial scientists trying to help better understand disease-causing proteins and motivate the development of new treatments for those particular diseases.
“While BromoTag can be used in by both academic and industrial scientist as of now, we plan to build on this work to develop updated more powerful versions to ask key biological questions and reveal functional and therapeutic insights.”
The paper is published in the Journal of Medicinal Chemistry.
The University is one of the world leaders in targeted protein degradation, a field of research that is revolutionising drug discovery and which has received billions of pounds of investment in recent years. This approach is making the treatment of diseases previously thought to be undruggable a reality.
Dundee researchers and teams led by CeTPD Director Professor Alessio Ciulli have previously revealed fundamental insights into the working of the degrader molecules that they have designed and that are used across the globe.
Degrading rather than inhibiting a target protein offers several advantages such as more efficacious drug response at lower doses, and a more targeted intervention with potentially reduced side effects and disease resistance. The first compounds in this class, termed Proteolysis-targeting chimeras (PROTACs), are being trialled as candidate medicines against various diseases and progressing through clinical trials.