We always welcome considering interested and motivated students to embark on their PhD in our laboratory. You are encouraged to familiarize yourself with the PhD Programme hosted within our School of Life Sciences at Dundee. If you want to learn more about our research and are considering joining our group for a PhD starting from 2019, do not hesitate to contact Alessio directly by e-mail.
Available Openings (New: March 2022)
About the Project
Proteolysis targeting chimeras (PROTACs) are a popular class of bifunctional molecules that simultaneously engage a target protein on one end and an E3 ubiquitin ligase on the other end, forming a ternary complex that facilitates the rapid ubiquitylation and subsequent degradation of the target protein. PROTACs are revolutionizing drug discovery and therapeutic development by destroying rather than merely inhibiting a target protein. PROTACs leverage a novel unique modality of chemical intervention that we call “induced-proximity” – whereby the small molecule recruits a target protein close to an enzyme, inducing non-cognate protein-protein interactions between the two and as a result driving downstream chemistry to occur on the target protein as neo-substrate.
With this Studentship we seek to harness the principles of the mode of action of PROTACs via the ternary complex to develop and characterize a novel class of heterobifunctional molecules that bring the target protein into proximity to enzymes of a different class from E3 ligases – namely enzymes that natively regulate phosphorylation of substrate proteins. These molecules have the potential to expand the ways in which undruggable proteins can be targeted for proximity-induced chemistry beyond PROTACs, thereby significantly advance research and therapy.
The project will explore and test the hypothesis that specific targeted (de)phosphorylation will be different and potentially advantageous over and above conventional inhibition of target protein kinases or phosphatases. That is because it is expected to leverage specific from proximity-induced ternary complexes, and because modulating specific target phosphorylation level will be expected to fine-tune signaling pathways in a more precise way and without pathway re-wiring that e.g. kinase inhibitors are typically susceptible to. Furthermore, it is anticipated that such an approach of inducing proximity at sub-stoichiometric level for catalytic gain of function chemistry, will spare other functions of the target protein in ways that for example is not possible with targeted protein degradation where the entire protein is removed from cell.
The Ciulli Lab is one of the pioneering laboratories in the fields of PROTACs. The lab has innovated and qualified several popular and high-profile chemical probes protein-protein interactions and protein degradation, including VHL inhibitor VH298 and VHL degrader CM11, and BET protein degraders MZ1 and trivalent PROTAC SIM1. These are widely used by the scientific community as benchmark tool compounds to study biology. The Ciulli lab contributed to the field the first ever crystal structure of a ternary complex between a PROTAC and its E3 ligase and target proteins, illuminating unprecedented structural and mechanistic insights and guiding principles of how such bifunctional molecules work.
The Sapkota lab has expertise in studying reversible phosphorylation of proteins and pathways underpinning the regulation of cell signalling processes which account for many human diseases, including cancer and neurodegenerative diseases. The Sapkota lab developed an affinity directed protein missile (AdPROM) system that allows for rapid and efficient destruction of endogenous target proteins in cell lines. More recently, they have adapted the AdPROM system to induce proximity to protein phosphatases as a means to achieve robust targeted dephosphorylation of divergent set of proteins.
Deadline: Friday, April 29, 2022
MSC by Research Programme - Bringing proteins together with small molecules
Recent advances from the Ciulli Lab and others have contributed to the establishment of a game-changing new modality of chemical intervention into biological system – one that goes significantly beyond the state-of-the-art. Instead of blocking a target protein with conventional inhibitors, we are now designing and studying “tailored” molecules, bivalent conceptually and in function, that bring proteins together by forming stable and cooperative ternary complexes. We have shown that this key ternary recognition feature allows for fast and effective induce proximity-driven chemistries, specifically protein ubiquitylation and subsequent proteasomal degradation. We are beginning to understand the rules of how to design and study this new class of molecules in order to best trigger specific downstream signaling events, with profound biological consequences and attractive therapeutic potential.
Our research in this area takes a multidisciplinary approach including organic and medicinal chemistry and computational tools to design and achieve desired molecules; structural biology and biophysics to study binary and ternary complexes in solution and reveal their structural and dynamic interactions; and chemical biology, biochemistry, proteomics and cell biology to study the cellular impact of our small molecules into relevant cellular systems – for example cancer cells sensitive to the knockdown of the protein target in question. Our science takes advantage of latest technologies and vast expertise available at the School of Life Sciences e.g. within the FingerPrint Proteomics Facility and the Drug Discovery Unit that we have access to. We collaborate with several research groups within the School, including the Divisions of MRC-PPU, GRE, and CSI, to deploy our bivalent molecules to interrogate the biology of targets of interest and to dissect the functional consequences of disrupting the signaling networks in which they are involved.
A one-year Master project would typically fit as part of on-going projects and research interests of the Lab. Importantly; it can be tailored to the student specific interests and motivations. If you are interested in joining the lab and contributing to our science in this exciting new area, to learn more about our work and to discuss potential opportunities, do not hesitate to get in touch with Alessio.
Please see our website for further details and how to apply - https://www.dundee.ac.uk/study/pgr/life-sciences-msc-research/
Applications can also be submitted via Find-a-PhD.com
References
Gadd, M. S. et al. (2017) Nat. Chem. Biol. 13, 514-521.
Maniaci, C. et al. (2017) Nat. Commun. 8, 830.
Hughes, S.J., and Ciulli, A. (2017) Essays in Biochem. 61, 505-516.
Maniaci, C., and Ciulli, A. (2019) Curr Opin Chem. Biol. 52, 145-156.
Please keep checking these pages for update, and feel free to contact me for informal enquiries