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(EPSRC DTP) Novel ruthenium catalysts for drug discovery of DNA damage response inhibitors

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  • Full or part time
    Dr C.K Schmidt
    Prof I Larrosa
    Dr L Tabernero
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The DNA damage response (DDR) harbours a plethora of eminently druggable targets that could lead to the treatment of cancer, ageing and associated diseases. However, despite the advances in biological understanding, progress has been slow in finding and optimising suitable small molecule drugs for many of these targets. This is partially due to the narrow section of chemical shape space that is currently commonly explored in the drug discovery process, due to the overreliance on a very small set of reactions that have traditionally been favoured over the past 20 years. In recent years, C-H functionalization has emerged as an extremely promising new synthetic tool that could accelerate drug discovery by allowing fast access to new chemical space through the direct modification of existing drugs or biologically active molecules at their C-skeleton structure. However, the adaptation of C-H functionalisation tools to achieve this proposed ‘late-stage functionalisation’ faces major challenges in that most transition metal catalysts are incompatible with the highly polar functionalities present in biologically active molecules.

In a collaborative effort between the Schmidt group at the Manchester Cancer Research Centre (MCRC), the Larrosa group at the School of Chemistry and the Tabernero group in the Michael Smith Building (MSB), this project will focus on the development of a new class of ruthenium-catalysts recently discovered in the Larrosa group, which are able to carry out late-stage C-H functionalisation on heavily functionalised molecules such as pharmaceuticals, biologically active molecules and drug candidates. These catalysts will be used to create novel libraries of drug candidates across currently barely explored chemical shape space with the aim of targeting DNA repair pathways.

The successful applicant will receive state-of-the-art training on all aspects of the project, including organometallic chemistry, catalysis, synthetic chemistry, generation of compound libraries and on drug discovery approaches. Moreover, the appointee will be trained in the biological aspects of the work, such as cell proliferation, DNA repair and biochemical assays, as well as tissue culture techniques and advanced microscopy approaches.


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.

On the online application form select PhD Drug Design, Development and Delivery. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/)

Funding Notes

EPSRC DTP studentship with funding for a duration of 3.5 years to commence in September 2019. The studentship covers UK/EU tuition fees and an annual minimum stipend (£15,009 per annum 2019/20). Due to funding restrictions the studentship is open to UK and EU nationals with 3 years residency in the UK.

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

Schmidt, C. K., Galanty, Y., Sczaniecka-Clift, M., Coates, J., Jhujh, S., Demir, M., Cornwell, M., Beli, P., and Jackson, S. P. (2015). Systematic E2 screening reveals a UBE2D–RNF138–CtIP axis promoting DNA repair. Nat. Cell Biol. 17, 1458–1470.
• IF 19, ranked 5th/187 in Cell Biology excluding reviews

Xi, W.*, Schmidt, C.K.*, Sanchez, S., Gracias, D.H., Carazo-Salas, R.E., Butler, R., Lawrence, N., Jackson, S.P., and Schmidt, O.G. (2016). Molecular insights into division of single human cancer cells in on-chip transparent microtubes. ACS Nano 10, 5835–5846.
• This article demonstrates experience of the primary supervisor to successfully train physical sciences & engineering researchers in interdisciplinary work with biological sciences.
• IF 14, ranked 3rd/85 in Nanoscience & Nanotechnology excluding reviews

Aymard F, Bugler B, Schmidt C. K., Guillou E, Caron P, Briois S, Iacovoni J. S., Daburon V, Miller K. M., Jackson S. P., Legube, G. (2014). Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat. Struct. Mol. Biol. 21, 366–374.

Simonetti, M., Cannas, D. M., Just-Baringo, X., Vitorica-Yrezabal, I., Larrosa, I.* (2018). A Cyclometalated Ruthenium-catalyst enables late stage functionalisation of pharmaceuticals. Nat. Chem., 2018, 724–731.
• IF 26, ranked 1st for original research in Chemistry

Simonetti, M., Perry, G. J. P., Cambeiro, X. C., Larrosa, I.* (2016). Ru-Catalyzed C–H arylation of fluoroarenes with aryl halides. J. Am. Chem. Soc. 138, 3596-3606.
• IF 14, ranked 2nd for original research in Chemistry



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