MRC Protein Phosphorylation and Ubiquitylation Spotlight Seminar
We have a special seminar by George Burslem from Yale University, who has applied for a PI position within the School of Life Sciences and has been undertaking PROTAC-related projects to study the targeted degradation of receptor Tyrosine kinases. This work has been undertaken in the laboratory of Craig Crews who, along with Alessio Ciulli, is a world-leader in the PROTAC biology/chemistry field. George wishes to set up a laboratory to better study the regulation and function of deubiquitylases using novel chemical probes that he plans to design and synthesise. This should be an interesting seminar where George will present his current work as well as his future plans, which will be of wide interest to those working on signalling pathways, chemical biology, and PROTAC-related research.
Proteolysis Targeting Chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. The development of PROTACs for receptor tyrosine kinases, a protein family previously thought to be intractable for induced protein degradation, will be described. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone including more potent inhibition of cell proliferation, a more durable and sustained downstream signalling response and in vivo degradation. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach.
Furthermore, the role of favourable protein-protein interactions in the development of potent PROTACs will be described. Using promiscuous PROTACs that bind >50 kinases, we show that only a subset of bound targets are degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein. Weak PROTAC:target protein affinity can be stabilized by high affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation.
‘Targeted Protein Degradation of Receptor Tyrosine Kinases
Monday, February 11, 2019 - 15:30
Small Lecture Theatre, Medical Sciences Institute, School of Life Sciences
Professor Dario Alessi FRS FRSE FMedSci
Dr George Burslem
University of Yale