Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, β-catenin, and FoxP3

Targeted protein degradation (TPD), induced by enforcing target proximity to an E3 ubiquitin ligase using small molecules has become an important drug discovery approach for targeting previously undruggable disease-causing proteins. However, out of over 600 E3 ligases encoded by the human genome, just over 10 E3 ligases are currently utilized for TPD. Here, using the affinity-directed protein missile (AdPROM) system, in which an anti-GFP nanobody was linked to an E3 ligase, we screened over 30 E3 ligases for their ability to degrade 4 target proteins, K-RAS, STK33, β-catenin, and FoxP3, which were endogenously GFP-tagged. Several new E3 ligases, including CUL2 diGly receptor KLHDC2, emerged as effective degraders, suggesting that these E3 ligases can be taken forward for the development of small-molecule degraders, such as proteolysis targeting chimeras (PROTACs). As a proof of concept, we demonstrate that a KLHDC2-recruiting peptide-based PROTAC connected to chloroalkane is capable of degrading HALO-GFP protein in cells

‘Exchanges’:A visual resource to inspire and support deeper conversations in the Parkinson’s community

Interactions between people with Parkinson’s (PwP), carers and researchers are often limited to research talks or visits to laboratories. These interactions are hugely beneficial to all involved and improve the understanding of research developments, but the opportunity for deeper conversations – particularly around the complexities and ambiguities of the lived experience of Parkinson’s and of the research process itself – can be limited in these settings. We have developed and co-produced ‘Exchanges’, an interpretive art card resource with drawings that depict Parkinson’s research and symptoms alongside question prompts such as “What does Parkinson’s mean to you?” to support deeper conversations between PwP, carers and researchers.Initial experiences of the art card resource being used by a person with lived experience of Parkinson’s and a researcher generated striking levels of engagement, breaking down barriers and prompting deep, quality conversations about Parkinson’s. These powerful exchanges were captured on film.We also discovered that the resource has a wider impact than originally anticipated – it is incredibly successful at prompting discussion of the emotional and physical challenges of Parkinson’s between PwP and other PwP or carers too.Unexpectedly, the resource also supported profound conversations about Parkinson’s in a group setting as well as in pairs, with participant feedback advocating future use at conferences, in support groups and clinical settings.PwPs and researchers will present their experience of ‘Exchanges’ and why this is a valuable resource, not only to support patient involvement in Parkinson’s research, but to support the Parkinson’s community as a whole