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(BBSRC DTP) Development of anti-cancer agents and biomarkers that target intrinsically disordered regions of transcription factors and protein kinases


Project Description

The controlled manipulation of transcription factors, protein kinases and protein phosphatases is central to improving our understanding of cellular processes and, importantly, in the development of next-generation therapeutics for a variety of cancers. These protein classes make up a large proportion of current drug discovery portfolios in the pharmaceutical and biotech sectors. Like many involved in intracellular processes, these proteins are often either entirely intrinsically disordered or contain extensive intrinsically disordered regions. The selective modulation of their activity through manipulation of their intrinsically disordered regions is a highly attractive approach since it circumvents the well-known problems of trying to target active sites that are insufficiently distinct from those of many other proteins, leading to low specificity, and trying to interfere directly with large protein-protein interfaces.
We have very recently developed novel technology for the identification of unique transient structured regions within intrinsically disordered regions of proteins (Panova et al., Structure 2019 27 1-10), which can be targeted by either classical small molecule therapeutics, or by biotherapeutics, such as monoclonal antibodies. In this study, we will build on this breakthrough to discover small molecules and antibodies that target specific transcription factors and protein kinases, and determine the consequences of interfering with their function in vitro and in vivo. Our first target will be the oncogene Myc, which is a highly prized cancer target for our collaborators in the pharmaceutical industry. During the PhD, the student will gain experience in a wide variety of skills, ranging from specific monoclonal antibody production and selection, in vitro and in vivo activity assays, state-of-the-art spectroscopic, NMR and computational approaches to determining protein behaviour, structural biology and drug screening.

https://www.research.manchester.ac.uk/portal/j.waltho.html
https://www.research.manchester.ac.uk/portal/en/researchers/andrew-almond(29c9a6d5-74ea-4f38-8106-e437a0c116b0)/projects.html?period=running

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

[1] Assessing the Influence of Mutation on GTPase Transition States using X-ray, 19F NMR, and DFT Approaches. Jin Y, Molt RW Jr, Pellegrini E, Cliff MJ, Bowler MW, Richards NG, Blackburn GM, Waltho JP. Angew Chem Int Ed Engl. (2017) 56 9732-5.
[2] Myc Phosphorylation in the Basic Helix-Loop-Helix Inhibits Binding to Max and DNA via Destabilization of Transient alpha-Helical Structures. Macek P, Embrey KJ, Holdgate GA, Nissink JWM, Panova S, Cliff MJ, Waltho JP, Davies RA. J. Biol. Chem. (2018) 293 9301-9310.
[3] Van der Waals Contact between Nucleophile and Transferring Phosphorus Is Insufficient To Achieve Enzyme Transition-State Architecture. Johnson LA, Robertson AJ, Baxter NJ, Trevitt CR, Bisson C, Jin Y, Wood HP, Hounslow AM, Cliff MJ, Blackburn GM, Bowler MW, Waltho JP. ACS Catalysis (2018) 8 8140-8153.
[4] Equatorial active site compaction and electrostatic reorganization in catechol-O-methyltransferase. Czarnota S, Johannissen LO, Baxter NJ, Rummel F, Wilson A, Cliff MJ, Levy CW, Scrutton NS, Waltho JP, Hay S. ACS Catalysis (2019) 9 4394-4401.
[5] Mapping hidden residual structure within the Myc bHLH-LZ domain using chemical denaturant titration. Panova S, Cliff MJ, Macek P, Blackledge M, Ringkjøbing Jensen M, Nissink JWM, Embrey KJ, Davies R, Waltho JP. Structure (2019) 27 1-10.

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