Using CryoEM to trap and visualise PROTAC drugs in action against cancer targets


   Department of Chemistry

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  Dr James Hodgkinson, Dr John Schwabe  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

We invite applicants for a 4-year iCASE studentship to work in collaboration with our industrial partner Peak Proteins, part of Sygnature Discovery

Additional Supervisor: Emma Hesketh, University of Leicester

This PhD project is an exciting opportunity to explore the innovative drug strategy involving proteolysis targeting chimeras (PROTACs) using Cryo-Electron microscopy, a cutting-edge structural biology technique, at the University of Leicester. The project is in collaboration with a world-leading drug discovery CRO. PROTACs are novel bi-functional drugs that promise to ‘drug the undruggable’ by marking target proteins for degradation rather than inhibition. The proteins SOS1, a guanine nucleotide exchange factor, and LSD1, a lysine histone demethylase, are important cancer therapeutic targets with substantial prospects for future drug development.

SOS1 plays an essential role in the KRAS signalling pathway. Inhibitors of SOS1 have shown considerable potential for targeting RAS-driven tumours.  LSD1 plays a critical role in the endothelial to mesenchymal transition that is a key step in allowing tumours to metastasize. Inhibition of LSD1 has been shown to be a promising treatment for melanoma. To determine the structure-activity relationship of these PROTACS, you will use state of the art cryo-electron microscopy at the regional facility based at Leicester, and chemically synthesise novel PROTACs for evaluation using cryo-electron microscopy. In partnership with the drug discovery CRO you will learn interdisciplinary techniques in medicinal chemistry, protein expression/purification and structural biology amongst industry experts.

Enquiries

Project Enquiries to [Email Address Removed] 

Programme enquiries to [Email Address Removed]

To apply please refer to

https://more.bham.ac.uk/mrc-aim/phd-opportunities/


Biological Sciences (4) Chemistry (6) Medicine (26)

Funding Notes

The competition funding provides students with:
4 years of stipend at UKRI rates
4 years of tuition fees at UK fee rates (Plus one award of a full overseas fee waiver to an international applicant)*
RTSG
Budget to help with the cost of purchasing a laptop
The University of Leicester will provide full overseas fee waivers for the duration of their study to all international students accepted at Leicester. The funder, UKRI, allows us to appoint up to 30% overseas students.

References

Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs), I.M. Baker, J.P. Smalley, K.A. Sabat, J.T. Hodgkinson, S.M. Cowley, Biochemistry, 2023, 62, 645.
Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells, J.P. Smalley, I.M. Baker, W.A. Pytel, L.Y. Lin, K.J. Bowmann, J.W.R. Schwabe, S.M. Cowley, J.T. Hodgkinson, J. Med. Chem. 2022, 65, 5642-5659.
A ‘Click’ Chemistry Approach to Novel Entinostat (MS-275) based Class I Histone Deacetylase Proteolysis Targeting Chimeras, J. M. Cross, M. E. Coulson, J. P. Smalley, W. A. Pytel, O. Ismail, J. S. Trory, S. M. Cowley, J. T. Hodgkinson, RSC Med. Chem., 2022, 13, 1634.
HDAC Degrader, S. M. Cowley, J. T. Hodgkinson, J. W. R. Schwabe, J. P. Smalley, G. E. Adams, C. J. Millard, WO application 2021148811 (A1) , published 29.07.2021
PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes, J. P. Smalley, G. E. Adams, C. J. Millard, Y. Song, J. K. S. Norris, J. W. R. Schwabe, S. M. Cowley, J. T. Hodgkinson, Chem. Commun., 2020, 56, 4476-4479.
Functional and structural coupling between LSD1 and HDAC1 in the CoREST complex. Song Y., Dagil l., Fairall L., Robertson N., Wu M., Ragan T.J., Savva G.C., Morone N., Kunze M.B.A., Jamieson A.G., Cole P.A., Hansen D.F., Schwabe J.W.R. (2020) Cell Reports 30, 2699.
Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors Kalin, J.H., Wu, M., Gomez, A.V., Song, Y., Das, J., Hayward, D., Adejola, N., Wu, M., Panova, I., Chung, H.J., Kim, E., Roberts, H.J., Roberts, J.M., Prusevich, P., Jeliazkov, J.R., Roy Burman, S.S., Fairall, L., Milano, C., Eroglu, A., Proby, C.M., Dinkova-Kostova, A.T., Hancock, W.W., Gray, J.J., Bradner, J.E., Valente, S., Mai, A., Anders, N.M., Rudek, M.A., Hu, Y., Ryu, B., *Schwabe, J.W.R., *Mattevi, A., *Alani, R.M., *Cole, P.A., (2018). Nature Communications, (2018) 9(1), 53. http://doi.org/10.1038/s41467-017-02242-4. *Co-corresponding authors
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