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Probing the Chemical Space of Heterobifunctional Molecules Targeting the Epigenome (GTA 20 HOD)


Project Description

The development of new chemical tools and probes is vital to understanding the functions of multifaceted proteins and enzymes in the cell and their role in disease. Many enzymes catalyse chemical modifications to DNA and DNA associated proteins regulating which genes are ‘switched on’ and ‘off’, often termed the epigenome. Histone deacetylases (HDAC) are a class of enzyme that remove acetyl groups from DNA associated histone proteins. The presence of many HDAC isoenzymes in the cell, with structural similarity, makes probing these enzymes selectively a challenge. Further to this, the same HDAC isoenzyme can be incorporated as a catalytic sub-unit into a number of much larger multiprotein complexes, whereby the complex is essential to the distinct biological function of the HDAC. Abnormal HDAC activity is associated with diseases including cancer and Alzheimer’s yet current drugs on the market lack HDAC enzyme selectivity and are associated with debilitating side effects.

The studentship entails exploring the chemical space of novel heterobifunctional molecules towards gaining selectivity for specific HDAC multiprotein complexes. This will be achieved by the chemical synthesis of libraries of novel heterobifunctional molecules and their biological evaluation. This research advances and expands further on our recent findings in which we have identified heterobifunctional molecules capable of selectively engaging the HDAC enzymes that are present in complexes (EPSRC grant; EP/S030492/1; PI J.T. Hodgkinson). The studentship is in collaboration between the groups of Dr Hodgkinson (School of Chemistry and Leicester Institute of Structural and Chemical Biology), Professor Shaun Cowley (Department of Molecular and Cell Biology). The appointed candidate will gain in-depth skills and training in synthetic organic chemistry, medical chemistry, and cell biology preparing the candidate for a future career in academia in the chemical biology research area or the pharmaceutical industry.

Methodology

- Modern synthetic organic chemistry techniques will be used to synthesise heterobifunctional molecules (synthetic lab, chemistry & LISCB, JTH).

- Analysis and full characterisation of the heterobifunctional molecules will be carried out using modern analytical techniques including NMR spectroscopy and mass spectrometry (analytical labs, chemistry & LISCB, JTH).

- Combinatorial chemistry techniques will be used to prepare a library of analogues with various modifications (synthetic lab, chemistry & LISCB, JTH).

- The libraries will be screened against various purified HDAC multiprotein complexes in model systems (LISCB, JTH)

- The libraries will be screened against a panel of cancer cell lines and complex selectivity determined (Cowley lab, Molecular and Cell Biology)

Academic entry requirements

UK Bachelor Degree with at least 2:1 in a relevant subject or overseas equivalent.

University of Leicester English language requirements apply (where applicable).

UK/EU applicants only.

Application Instructions

When applying, please ensure we have received all of the following required documents by Tuesday 4th February 2020 :

- Application Form
- 2 academic references
- CV
- Undergraduate transcripts

If you have completed your undergraduate degree, we will also require your undergraduate degree certificate.
If you have completed a postgraduate degree, we will also require your transcripts and degree certificate.

If we do not have the required documents by the closing date, your application may not be considered for the studentship.

Please refer to guidance at - https://le.ac.uk/study/research-degrees/funded-opportunities/chem-gta-2020

Funding Notes

Fully funded 4 years.

UK/EU tuition fee waiver.

Stipend at UKRI rates.

References

1. K.J. Falkenberg & R. W. Johnstone, Nat. Rev. Drug Discov, 2014, 13, 673.
2. M. Guha, Nat. Rev. Drug Discov, 2015, 14, 225.
3. W. Weichert, Cancer. Lett. 2009, 280, 168.
4. C.J. Millard et al. Trends Pharmacol. Sci., 2017, 38, 363.

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