Construction and Biological Characterisation of a Custom Engineered Protein Degradation Tool
Lead Research Organisation:
University of Cambridge
Department Name: Pharmacology
Abstract
Development of non-small molecule drugs has expanded over recent years, with biologics such as antibodies now seen as a viable treatment for some diseases. Protein and peptide drugs benefit from higher specificities than small molecules, and there is a much wider range of targets to which they can be applied. One such target is Aurora Kinase A, which is overexpressed in many cancer types and acts as a driver of cancer by phosphorylating substrates. AURKA is overexpressed in cancers such as breast, colon and neuroblastomas and targeting AURKA by inhibition does affect cancer growth but there is not complete reversal of the cancer phenotype. Targeting AURKA for degradation using the ubiquitin-proteasome system has potential for a better clinical response. PROTACs (PROteolysis Targeting Chimeras) are a new class of drug, that induce degradation of target molecules via a bifunctional small molecule, with a flexible linker region in the middle. Degradation occurs via the Ubiquitin Proteasome System, using chains of ubiquitin as the signalling molecule.
There are a range of scaffolds used in this work, including TetratrioPeptide Repeats, Recombinase ATPase domain, and Monobodies. These scaffold proteins have AURKA binding regions inserted and degrons that bind E3 ligases elsewhere in the sequence. These bifunctional molecules should induce Aurora A degradation using the Ubiquitin Proteasome System. Work has been preformed using cancer cells treated with these constructs, and biophysical work to characterise their structure and interactions.
There are a range of scaffolds used in this work, including TetratrioPeptide Repeats, Recombinase ATPase domain, and Monobodies. These scaffold proteins have AURKA binding regions inserted and degrons that bind E3 ligases elsewhere in the sequence. These bifunctional molecules should induce Aurora A degradation using the Ubiquitin Proteasome System. Work has been preformed using cancer cells treated with these constructs, and biophysical work to characterise their structure and interactions.
Organisations
Publications
Davey MP
(2019)
Snow algae communities in Antarctica: metabolic and taxonomic composition.
in The New phytologist
Description | Royal Society of cell biology meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Collaborators from Italy and France came to the UK for a small meeting. I presented work here for about 4 lab groups worth of people. |
Year(s) Of Engagement Activity | 2019 |
Description | STEM for BRITIAN |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Spoke to other postgraduates from other universities about my work and spoke to the MP for Cambridge, and through email spoke to the MP for Southgate too to encourage them to engage with science. The aim is to get MPs to engage with science more |
Year(s) Of Engagement Activity | 2020 |
URL | https://stemforbritain.org.uk/ |